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Preparation of a novel ginkgolide B niosomal composite drug

  • Juntong Zhou , Xiao Wu , Zhanhong Zhao , Zhenpeng Wang , Shumu Li , Chang Chen , Shan Yu , Xintong Qu , Kexin Li , Ye Tian , Xiaojing Liu , Gaoyu Zhang , Zhaoxuan Wang , Chi Li , Ning Kang and Qing Huo EMAIL logo
Published/Copyright: August 26, 2020
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Open Chemistry
From the journal Open Chemistry Volume 18 Issue 1

Abstract

Ginkgolide B (GB) and Puerarin (Pue) are active pharmaceutical ingredients for the treatment of Parkinson’s disease (PD); however, both are poorly water-soluble, which limits their bioavailability. The present study used the niosome vesicle encapsulation technique to prepare a novel GB composite drug. The conditions for GB–Pue niosomal complex preparation were as follows: a hydration temperature of 60°C, a hydrophilic–lipophilic balance of 10.5, a drug–carrier mass ratio of 8:100, and a surfactant–cholesterol mass ratio of 1.5:1. The niosomal complex suspension was uniformly distributed and milky white in color, with no stratification over a duration of 1 month. It had an average particle size of 187.3 nm, a particle-size distribution of 0.237, a GB encapsulation efficiency (EE) of 68.2%, a GB drug-loading rate of 90.1%, a Pue EE of 40.5%, and a Pue drug-loading rate of 83.3%. The optimal storage temperature for the niosomal complex suspension was 4°C. Following an intravenous injection of the niosomal complex suspension into the rat tail, the area under the curve (AUC) from 0 to 4 h was 54.1 h µg mL−1, with a mean residence time (MRT) of 0.96 h, a distribution half-life (T1/2α) of 0.195 h, and a total clearance of 0.003 L h−1 kg−1. The AUC and MRT of the composite prescription were 1.1- and 1.4-times those of the commercial injection, respectively, showing significantly increased sustained release and bioavailability. Moreover, the distribution of GB in the brain tissue was 1.8-times that of the commercial injection. In conclusion, the novel GB niosomal composite drug, with excellent stability, improved pharmacokinetics, and brain tissue distribution, demonstrates great potential for the delivery of GB and Pue for PD therapeutics.

Keywords: ginkgolide B; puerarin; niosome; Parkinson’s disease

1 Introduction

Alzheimer’s disease (AD) is a progressive neurological degenerative disorder, the symptoms of which are not always apparent in the early stages. Currently, the well-recognized pathogenic mechanism of AD is thought to be a persistent abnormal increase in the level of glutamic acid in the brain. Glutamic acid activates G protein coupled receptors, which leads to the overproduction and aggregation of β-amyloid (Aβ), destroying neurons and eventually resulting in neurodegenerative diseases [1,2,3]. Alberdi et al. reported that ionized glutamic acid may induce abnormal calcium changes, cause Aβ overload, sabotage mitochondrial function, escalate intracellular oxidative stress, promote depolarization of the mitochondrial membrane, and eventually result in neurotoxicity.

Ginkgo biloba belongs to the Ginkgoaceae family and contains a variety of effective therapeutic factors such as flavonoid and terpenoid derivatives. Ginkgolide B (GB) accounts for approximately 25% of the total ginkgolides. The efficacy of GB has been demonstrated via the inhibition of platelet-activating factor (PAF). GB is recognized worldwide as an effective substance for the treatment of brain diseases, with only mild adverse effects [4,5,6,7]. Intervention with GB has been shown to protect nerve cells damaged by the accumulation of Aβ from further destruction [8,9]. Using in vitro experiments, Xiao et al. showed that GB can diminish the induction of apoptosis by the Aβ (25–35) peptide, suggesting that the mechanism may involve brain-derived neurotrophic factor [10]. Shi et al. indicated that GB has protective and reparative effects on mitochondria damaged by the Aβ (1–42) peptide, in addition to interfering with the activation of amino-terminal kinases and the transmission of abnormal signals in the brain. Currently, GB substances with PAF receptor antagonistic effects are considered capable of effectively interfering with the development of AD and could therefore be used for the treatment of early-stage AD [11,12]. Conventional GB prescriptions include emulsions, powder injections, solid dispersion in the form of dripping pills, and powders. Oral GB liposomes are on the market in Europe to protect the heart and brain blood vessels in the elderly; however, the physicochemical properties of GB, such as high hydrophobicity and high molecular weight, markedly decrease its bioavailability.

Pueraria belongs to the Leguminosae family of herbs and its primary active ingredients are flavonoids such as daidzein and puerarin (Pue). The isoflavone of Pue is key to its pharmaceutical applications. Pue has significant positive effects on neurological diseases in the brain, such as AD and Parkinson’s disease (PD); however, its therapeutic mechanism is extremely complicated, likely involving three different processes. The first is stabilizing the functions of amino acid neurotransmitters; Pue can maintain the dynamic balance of excitatory and inhibitory amino acids and eliminate nerve cell damage [13,14,15,16]. The second is scavenging free radicals; when the body has excessive free radicals, Pue can activate endogenous antioxidants to relieve nervous system damage. The third is interfering with the regulation of neural apoptosis signaling; under detrimental conditions such as ischemia, Pue can activate the PI3-K/Akt pathway and induce gene expression to reduce the degree of damage to neurons and nerve cells [17,18,19].

GB can affect the metabolism of glutamic acid and dopamine by regulating the d-glutamic acid pathway, thus interfering with the early stage of PD. Intervention of PD with Pue works primarily by increasing endogenous antioxidant activity, regulating calcium signaling pathways, and removing free radicals. The etiology of PD suggests that the structure of l-DOPA in the nigrostriatal area of the brain is affected, increasing the levels of dopamine and free radicals, which destroy the structure of neurons. The two abovementioned drugs can effectively regulate key points in the disease process, protecting and repairing neurons in the brain.

Niosome technology is a novel microparticle preparation method based on liposomes. Non-ionic surfactant niosomes use non-ionic surfactants to ensure that the vesicle excipients are structured as bilayers to encapsulate pharmaceuticals, and the number of structural layers of niosomes can be modified to encapsulate multiple pharmaceutical ingredients [20,21]. The special excipients of non-ionic surfactant vesicles can encapsulate both hydrophilic and lipophilic drugs, enhance their synergism, stabilize their curative effect, improve patient compliance, and avoid the oxidative decomposition issues related to phospholipid molecules [22]. Niosomes are used as an emerging drug delivery system that is in phase III and IV trials in Germany due to the sustained, controlled, and targeted release, convenient administration, good patient compliance, and treatment efficacy for a variety of conditions. During the preparation of niosomes, external forces such as ultrasound and pressure are needed to form the bilayer structure; the hydrophilic–lipophilic balance (HLB) and amphiphilic molecular conformation are key to regulating its formation. Moreover, the inter-bilayer spacing, preparation process, bilayer fluidity, and number of chains in the bilayer structure can also play a role in sustained drug release and targeting. The size of the non-ionic surfactant vesicles is important for allowing passage through various tissues and organs, eliminating the first-pass effect, and penetrating the blood–brain barrier. Modification of membrane materials mainly focuses on the location of the modification and whether it results in the expected targeting effects. Modifications include ferrous ions, strong volatile traditional Chinese herbs, and probes [23,24].

The blood–brain barrier can prevent various pharmaceuticals from reaching the brain, causing difficulties in the treatment of diseases. Using carriers that can facilitate penetration of the blood–brain barrier, such as modified ions, strong volatile Chinese herbs, and probes, helps to reach a drug concentration in its effective range and achieve brain targeting [25,26,27]. Previous studies have investigated strong volatile Chinese herbs and found that mint and gabardine can relax the endothelial cells constituting the blood–brain barrier, which temporarily enhances the permeability of pharmaceuticals.

There exist various pathogenic theories for PD. In the present study, three theories, oxidative stress, neurotoxicity, and dopamine abnormality, were used as references to select drugs and the site of action. By controlling the dynamic balance of dopamine, free radicals, and glutamic acid in multiple brain areas, the remission and treatment of PD could be achieved. While most of the available marketed drugs are a single-drug therapy, we attempted to target two sites for the treatment and control of PD by studying a composite drug of GB and Pue. GB could reduce the abnormal level of dopamine since it stimulates the conversion of l-DOPA to dopamine, and Pue could decrease the excessive level of free radicals since it acts as a scavenger. One of the primary reasons why many pharmacological treatments for PD fail to achieve the desired effect is their inability to cross the blood–brain barrier, which has a certain blocking effect on drug molecules above the nanoscale. Studies on traditional Chinese medicine have demonstrated that certain aromatic drugs have a temporary weakening effect on the blood–brain barrier, effectively allowing the drug to cross in the brain. In the present study, borneol was applied onto the niosomal bilayer to facilitate the uptake of the vesicles into the brain, allowing GB and Pue to exert their pharmacological effects.

In the present study, poorly water-soluble GB and Pue were used to prepare a novel brain-targeted drug. Glyceryl monostearate (GMS), MYRJ49, and cholesterol were employed as excipients to prepare niosomes encapsulating GB and Pue, and the niosome surfaces were modified with volatile borneol.

2 Materials and methods

2.1 Experimental materials

GB (93% content), GB standard, Pue (90% content), and Pue standard were purchased from Sichuan Pharmaceutical Co., Ltd (Sichuan, China). GMS was purchased from Guangzhou Kafen Biotech Co., Ltd. MYRJ 49 was purchased from Guangzhou Donglin Fine Chemical Co., Ltd. Cholesterol, glucose, sodium chloride, dimethyl sulfoxide (DMSO), and Tween® 80 were purchased from Beijing Mengyimei Bio-Tech Co., Ltd. Borneol was purchased from Shanghai Puda Chemical Co., Ltd. A total of 20 male Wistar rats, weighing 200 ± 20 g and fed a standard diet, were used. All animals and feed were obtained from the Beijing University of Traditional Chinese Medicine.

2.2 Experimental instrumentation

The following instrumentation was used: high-performance liquid chromatography (HPLC) 1200 system (Agilent Technologies); rotary evaporator RE-2000 (Shanghai Yarong Biochemical Instrument Factory); low-temperature cooling liquid circulating pump (Zhengzhou Greatwall Scientific Industrial and Trade Co., Ltd); high-pressure homogenizer (Shanghai Shenlu Homogenizer Co., Ltd); ultrasonic cell pulverizer (Ningbo Scientz Biotechnology Co., Ltd); zetasizer (Malvern Instruments, UK); comprehensive drug stability test chamber (Hangzhou Junsheng Scientific Equipment Co., Ltd); CO2 cell culture incubator (Suzhou Proxy Water Experiment Equipment Co., Ltd); inverted phase contrast microscope (Shanghai Yuyan Instruments Co., Ltd); ultra-high-performance liquid chromatograph mass spectrometer (UHPLC-MS) Shimadzu LCMS-8050 (Shanghai Yidian Analytical Instrument Co., Ltd).

2.3 Experimental methods

2.3.1 HPLC analysis of GB

The GB standard solutions were prepared and subjected to ultraviolet (UV) detection according to the Pharmacopoeia of the People’s Republic of China 2015 Edition. The HPLC settings were as follows: mobile phase of methanol:0.2% aqueous phosphoric acid solution = 33:67; flow rate of 1 mL/min; wavelength of 205 nm; column temperature of 30°C; and injection volume of 20 µL. The y-axis represented the GB peak area and the x-axis represented the GB standard concentration, resulting in a linear equation of y = 521.2x + 13.675, R2 = 0.9990, with a regression interval of 0.1–1.5 mg/mL (Figure 1).

Figure 1 GB standard solution
Figure 1

GB standard solution

2.3.2 HPLC analysis of Pue

The Pue standard solutions were prepared and subjected to UV detection according to the Pharmacopoeia of the People’s Republic of China 2015 Edition. The HPLC settings were as follows: mobile phase of methanol:0.5% aqueous phosphoric acid solution = 30:70; flow rate of 1 mL/min; wavelength of 264 nm; column temperature of 30°C; and injection volume of 20 µL. The y-axis represented the Pue peak area and the x-axis represented the Pue standard concentration, resulting in a linear equation of y = 53,511x − 2303.7, R2 = 0.9992, with a regression interval of 0.1–1.5 mg/mL (Figure 2).

Figure 2 Pue standard solution
Figure 2

Pue standard solution

2.3.3 Preparation of the niosomal complex suspension

  1. Appropriate amounts of GMS, MYRJ 49, and cholesterol were dissolved in a homogeneous mixture of DMSO:methanol (1:3) and subjected to reduced pressure at 55°C until all solvents had volatilized to leave a thin film.

  2. The prepared thin film was dissolved in an appropriate amount of organic reagent, added to alcohol and buffer containing an appropriate amount of drug (GB–Pue mass ratio of 1:1), and shaken for 20 min. Subsequently, an appropriate amount of buffer was added and hydration was carried out for 15 min, followed by the addition of borneol at room temperature.

  3. The niosomal complex suspension was further homogenized using a high-pressure homogenizer (1,000 bar, four times).

Note: Phosphate-buffered saline (PBS) (pH = 6.8); a precise volume of 250 mL of 0.2 mol/L potassium dihydrogen phosphate solution and 118 mL of 0.2 mol/L aqueous sodium hydroxide solution were transferred to a 1 L volumetric flask and distilled water was added to a final volume of 1 L; borneol was pulverized using a mortar and pestle; the surface active agent in Table 1 was Reviewer #1-(a mixture of GMS and MYRJ 49; the carrier was surfactant (GMS and MYRJ 49) and cholesterol.

Table 1

Factors and levels of orthogonal experimental design

LevelsFactors
(A) Temperature (°C)(B) Surfactant–cholesterol ratio(C) Drug–carrier ratio(D) HLB
1501.25:18:10010.0
2551.50:19:10010.5
3601.75:110:10011.0

Scoring criteria:

  1. The scoring of encapsulation efficiency (EE): 80% = 40 points.

  2. The scoring of drug loading: 60% = 30 points.

  3. The scoring of particle size: (0.05–0.10] µm = 20 points; (0.10–0.15] µm = 16 points; (0.15–0.20] µm = 12 points; (0.20–0.25] µm = 8 points; (0.25–0.30] µm = 4 points; (0.30–0.50] µm = 2 points; and >0.50 µm = 0 points.

  4. The scoring of PDI: (0.05–0.10] = 10 points; (0.10–0.15] = 8 points; (0.15–0.20] = 6 points; (0.20–0.30] = 4 points; (0.30–0.50] = 2 points; (0.50–1.00] = 1 point; and >1 = 0 points.

2.3.4 Evaluation of the niosome quality

2.3.4.1 EE of niosomes

  1. The niosomal suspension was transferred to a centrifuge tube using a pipette and centrifuged at 4,000 rpm for 20 min. The upper layer was collected and diluted to obtain Wf.

  2. An appropriate amount of the lower layer was transferred to a centrifuge tube using a pipette, demulsified with methanol, shaken thoroughly, diluted, and filtered through a microporous membrane to obtain Wi.

EE(%)=Wi/Wf+Wi×100
2.3.4.2 Drug loading

  1. The niosomal suspension was transferred to a centrifuge tube using a pipette, to which an appropriate amount of methanol was added. The solution was transferred to a homogenizer to break the vesicles.

  2. The above solution was filtered through a microporous membrane to measure the total drug concentration Wt.

2.3.4.3 Storage condition testing

GB, Pue, and the GB–Pue niosomal complex suspension were placed at 4°C and 25°C and stored in sealed glass bottles for 0, 7, 14, 21, 28, 35, and 60 days.

2.3.5 In vivo pharmacokinetics and brain distribution of the niosomal complex suspension in rats

In the present study, the route of administration was intravenous bolus injection in the rat tail. The concentration was 12.7 µg/mL GB for prescription 1 and 12.9 µg/mL GB for prescription 2. The administered volume was 4 mL (administered according to the dose) and the injection dose was 200 µg/kg.

Each experimental group contained six male Wistar rats that were fasted overnight for 12 h, weighed, and administered drugs according to weight. Approximately 0.8 mL of blood was sampled from the rat eye socket vein prior to administration and 5, 15, 30 min, and 1, 2, 3, and 4 h following administration. The blood sample was transferred to a heparin anticoagulant tube, centrifuged to prepare plasma, acidified with hydrochloric acid (100 µL of 1 mol/L hydrochloric acid per 1.0 mL plasma), and stored in a −20°C freezer. The present study was performed according to the international rules considering the animal experiments and biodiversity rights (Ethical Approval Council Number: 2020-02).

A volume of 10 µL fluconazole internal standard (10 µg/mL) was added to 0.2 mL acidified plasma sample and vortexed for 30 s, to which 1 mL of ethyl acetate was added, and the solution was shaken for 2 min and subsequently centrifuged at 6,000 rpm for 5 min. An 800 µL aliquot of the supernatant was dried under nitrogen at 40°C in a water bath. The 100 µL residual was dissolved in acetonitrile, vortexed for 30 s, and centrifuged, and the resulting supernatant was transferred to a HPLC vial.

2.3.6 Preparation of brain tissue samples

Prescription 1 contained 12.7 µg/mL GB and prescription 2 contained 12.9 µg/mL GB in an administered volume of 4 mL (same as above). The rats were euthanized by cervical dislocation 2 h after administration. The brain tissue was then extracted, rinsed with cold saline to remove the superficial blood and debris, wiped clean with dry tissues, and weighed. Subsequently, methanol was added to the brain samples at an overall sample–methanol ratio of 1:3, which were then subjected to homogenization for 15 clockwise and 15 counterclockwise rotations at a constant speed until a uniform milky white-colored homogenate formed. Volumes of 200 µL methanol and 10 µL fluconazole internal standard (10 g/mL) were added to 800 µL brain homogenate, vortexed for 1 min, and centrifuged at 12,000 rpm for 3 min. An 800 µL aliquot of the upper layer was dried under nitrogen. The 100 µL residuals were dissolved in acetonitrile, vortexed for 30 s, and centrifuged, and the resulting supernatant was transferred to a HPLC vial.

Note: Prescription 1: 0.025 mg GB, 0.2009 mg GMS, 0.2991 mg MYRJ 49, and 0.375 mg cholesterol. Prescription 2: 0.025 mg GB, 0.025 mg Pue, 0.2009 mg GMS, 0.2991 mg MYRJ 49, 0.375 mg cholesterol, and 5 mg borneol.

2.3.7 LC-MS analysis

The LC-MS analysis was conducted using a UHPLC-MS Shimadzu LCMS-8050 system consisting of a Shimadzu LC-30AD (including an LC 30A binary pump, an SIL-30AC autosampler, an SPD-M30A photodiode array detector, and a CTO-20AC column oven) and an 8050 triple quadrupole MS.

For liquid phase separation, a Phenomenex Kinetex® C18 column (100 mm × 2.1 mm i.d.: 2.6 µm) was used. The mobile phase was acetonitrile (A) and 0.2% formic acid in water (B), with a flow rate of 0.5 mL min−1, isocratic, and A:B of 35:65. The column temperature was set to 30°C, and the injection volume was 1 µL.

The MS parameters were as follows: a drying gas flow rate of 10 L min−1; a nebulization gas flow rate of 3 L min−1; a heating gas flow rate of 10 L min−1; an interface voltage of 3 kV; a detector voltage of 1.8 kV; an interface heater temperature of 300°C; a desolvation line temperature of 250°C; a block heater temperature of 400°C; ionization mode ESI negative; and MS mode multiple reaction monitoring.

A precise volume of 0.2 mL blank plasma was added to sequentially diluted GB standards to yield GB concentrations of 0.1, 0.5, 1, 5, 10, 100, and 500 µg/mL (seven samples). After processing as described in the plasma preparation method for HPLC, the samples were subjected to LC-MS with the settings as given in 2.3.6.5 at a wavelength of 207 nm. The y-axis represented the standard GB–fluconazole ratio and the x-axis represented the plasma GB concentration, resulting in a linear regression equation of y = 0.0159x + 0.006, R2 = 0.9999.

2.3.8 Statistical analysis of pharmacokinetics

Data were analyzed using DAS 2.0. WinNonlin was used to determine the area under the curve (AUC) from 0 to 240 min, biological half-life (T1/2), apparent volume of distribution (Vc), total clearance (CL), elimination rate constant from the central compartment (K10), distribution rate constant of the drug from the central to the peripheral compartments (K12), and distribution rate constant of the drug from the peripheral to the central compartments (K21).

3 Results and analysis

3.1 Effects of organic solvents on niosomal preparation

For the preparation of the niosomal complex suspension, GMS, MYRJ 49, and cholesterol were used as the vesicle excipients. In comparison with Tween® 80 and Span® 80 used in previous vesicle preparation studies, the excipients selected in the present study do not harm the human body over a wide range of concentrations, since GMS and MYRJ49 are food-grade materials primarily used in the manufacture of ice cream and cream, and are safe and non-toxic with no adverse effects.

As shown in Table 2, the two types of non-ionic surfactants, GMS and MYRJ 49, were both soluble in the listed organic solvents. Cholesterol dissolved well in diethyl ether, dichloromethane, and the dichloromethane–methanol mixed solvents. GB and Pue were soluble in methanol, ethanol, and diethyl ether, but did not dissolve well in dichloromethane. Considering both the excipients and drugs, the dichloromethane–methanol (1:3) mixture was selected as the experimental solvent.

Table 2

Screening of organic solvents

Organic reagentDissolving state
GMSMYRJ 49cholesterolGBPue
Methanol−−−++
Ethanol−−−++
Diethyl ether+++++
Acetone++−+−
Dichloromethane+++−−
Dichloromethane–methanol (1:1)+++−−
Dichloromethane–methanol (1:2)+++−−
Dichloromethane–methanol (1:3)+++++

Note: “−” represents incompletely dissolved and “+” represents completely dissolved.

3.2 Optimization of the niosomal complex suspension prescription

The hydration temperature, HLB, and non-ionic surfactant are important factors that affect the preparation of niosomes, which in turn determine the therapeutic effect of the encapsulated drugs. In addition, different prescriptions have an impact on the functional characteristics, such as hydrophilicity, lipophilicity, sustained release, and targeting.

On the basis of univariate analysis, orthogonal experiment design is shown in Table 1 to optimize the formulation and the results were obtained, as presented in Table 3. Orthogonal analysis of variance (ANOVA) was obtained, as presented in Table 4.

Table 3

Orthogonal table of the niosomal complex suspension prescriptions

No.FactorParticle size (nm)Particle size distributionTotal drug loading (%)Total EE (%)Overall score
ABCD
1501.25:18:10010159.450.32181.9260.6350.22
2501.5:19:10010.5142.650.26182.7649.9054.53
3501.75:110:10011199.80.32672.5549.8547.99
4551.25:19:10011345.90.32264.6535.4544.97
5551.5:110:10010250.10.34968.0538.9538.53
6551.75:18:10010.5174.350.31384.1350.4547.74
7601.25:110:10010.5155.250.31478.7846.8450.33
8601.5:18:10011246.60.16580.3749.8052.86
9601.75:19:10010283.850.34162.9137.5243.26
K154.7553.9257.1151.1
K245.6556.6949.5957.65
K357.9747.7751.6849.64
K12.328.927.528.01
FactorsA > B > D > C
Optimal combinationA3B2C1D2

Note: A is the hydration temperature; B is the surfactant–cholesterol mass ratio; C is drug–carrier ratio; and D is the HLB. The total EE and total drug loading were determined by the EE and drug loading of the two drugs together, R = R1/2 + R2/2.

Table 4

Orthogonal ANOVA of the EE of GB in the niosomal complex suspension

Type III sum of squaresDfMean squareFSig.
Temperature1603.0082801.504737.5800.000
Surfactant–cholesterol ratio48.401224.20122.2700.000
Drug–carrier ratio2031.03421015.517934.5250.000
HLB397.9812198.991183.1200.000

As shown in the ANOVA table of the niosomal complex suspension, the four factors, hydration temperature, surfactant–cholesterol mass ratio, drug–carrier mass ratio, and HLB, had significant effects on the mean particle size, particle-size distribution, EE, and drug loading, in the order of A > B > D > C. The optimal combination was A3B2C1D2, that is, a hydration temperature of 60°C, a surfactant–cholesterol mass ratio of 1.5:1, a HLB of 10.5, and a drug–carrier ratio of 8:100.

The hydration temperature used during the preparation process controls the arrangement of side branches in the niosomal bilayer. As the hydration temperature approaches the phase transition temperature of the membrane, the cross-sectional area of the bilayer becomes larger, the chromatographic intervals of the bilayer molecules are reduced, and the fluidity of the membrane is increased. The niosomes formed in this state have a superior drug loading, EE, and particle size. The non-ionic surfactant used in the present study contained no electrons, making the niosomes neutral and reducing the effect of external charges. However, a niosomal membrane composed of only surfactant would result in poor fluidity and instability. The addition of a certain amount of cholesterol would result in encapsulation in the bilayer to regulate membrane fluidity. Different compositions of non-ionic surfactants will produce pharmaceutical preparations with different HLB values. In the present study, the HPB of the pharmaceutical preparations was maintained in both the hydrophilic and lipophilic ranges, conducive to different clinical applications and expanding the scope of drug application. During niosomal complex suspension preparation, ultrasound and homogenization steps were included; the former dispersed the adhered vesicles and the pressure of the latter ensured a nanoscale vesicle particle size, providing an optimal particle dispersion.

All three batches of the prepared niosomal solution were milky white in color and showed no stratification (Figure 3). A small amount of niosomal suspension was placed on a slide, covered with a coverslip, and subjected to optical microscopy at a magnification of 1,000×. The morphologies are shown in Figures 4 and 5.

Figure 3 Niosomal complex suspension.
Figure 3

Niosomal complex suspension.

Figure 4 Microscopic morphology of blank niosomes (1,000×).
Figure 4

Microscopic morphology of blank niosomes (1,000×).

Figure 5 Microscopic morphology of niosomal complex suspension vesicles (1,000×).
Figure 5

Microscopic morphology of niosomal complex suspension vesicles (1,000×).

3.3 Storage conditions

As shown in Figure 6, the EE and physicochemical properties of the niosomal complex suspension were better preserved following storage at 4°C than at 25°C and demonstrated good stability. A low-temperature environment maintained the ordered arrangement and good fluidity of molecules in the bilayer, allowing the membrane to retain a stable framework and providing the niosomes with a higher stability.

Figure 6 EE stability of GB and Pue in the niosomal complex suspension.
Figure 6

EE stability of GB and Pue in the niosomal complex suspension.

3.4 In vivo pharmacokinetics and brain distribution of the niosomal complex suspension in rats

3.4.1 Pharmacokinetics

The niosomal complex suspension and commercial GB injections were intravenously administered to rats and the pharmacokinetic parameters of GB were determined. The pharmacokinetics of GB in rats were fit to a two-compartment model, as shown in Table 5 and Figures 7–9. Prescription 1 was a GB and Pue niosomal composite drug free of borneol; prescription 2 was a GB-, Pue-, and borneol-containing niosomal composite drug; and INJ was a commercial injection.

Table 5

Fitting to a two-compartment model

Pharmacokinetic parametersPrescription 1Prescription 2INJ
AUC0–4h (h µg mL−1)54.082 ± 8.20156.666 ± 12.80248.800 ± 6.80
Mean residence time (h)0.955 ± 0.1640.665 ± 0.430.706 ± 0.23
T1/2α (h)0.195 ± 0.1550.952 ± 0.1070.075 ± 0.05
T1/2β (h)2.153 ± 1.1990.883 ± 0.228*0.480 ± 0.21
K10 (h−1)15.313 ± 23.18513.758 ± 21.5694.542 ± 2.41
K12 (h−1)10.101 ± 17.4389.484 ± 16.0584.818 ± 3.59
K21 (h−1)1.061 ± 0.8072.259 ± 0.863*1.348 ± 1.09
Vc (L/kg)0.002 ± 0.0010.002 ± 0.0020.997 ± 0.48
CL (L h−1 kg−1)0.003 ± 0.0010.003 ± 0.0012.890 ± 1.63

Note: Each value represents the mean ± SD (n = 3). *p < 0.05 as compared with INJ.

Figure 7 Comparison of sustained release between the two prescriptions.
Figure 7

Comparison of sustained release between the two prescriptions.

Figure 8 Comparison of sustained release between prescription 1 and the commercial injection.
Figure 8

Comparison of sustained release between prescription 1 and the commercial injection.

Figure 9 Comparison of sustained release between prescription 2 and the commercial INJ.
Figure 9

Comparison of sustained release between prescription 2 and the commercial INJ.

Table 5 and Figures 7–9 display the mean GB concentration in plasma and variations in the pharmacokinetic parameters of GB within 4 h of intravenous injection. Prescriptions 1 and 2 exhibited no clear differences in the pharmacokinetic profile. Both niosomal complexes suspension demonstrated a significantly higher total GB concentration in plasma as compared with the commercial injection, and the AUC value for prescription 1 was 1.1-times that of the commercial injection, indicating that application of the niosome technique may significantly increase the bioavailability of drugs. The distribution half-life (T1/2α) and elimination half-life (T1/2β) of GB were also significantly enhanced as compared with those of the commercial injection, indicating that niosomes may be able to slowly release the drug in vivo. The decrease in CL indicates that the drug clearance was slowed and the residence time was increased.

Comparing prescription 1 with prescription 2, the T1/2α values indicate that prescription 1 absorbed slower, the MAT and T1/2β values indicate that prescription 1 stayed longer in the body, and the K21 values indicate that prescription 1 was distributed more slowly from the tissue to the blood, suggesting that the drug stayed longer in tissues and organs and was better targeted.

3.4.2 Distribution in the brain

Brain tissue was extracted and homogenized 2 h following the intravenous injection of GB niosomes in the rat tail, and the GB concentration in brain tissue was determined (Figure 10).

Figure 10 GB concentration in brain tissue.
Figure 10

GB concentration in brain tissue.

The GB concentration in the rat brain following the borneol-containing niosomal complex suspension, borneol-free niosomal complex suspension, and commercial injections was significantly different 2 h following the intravenous injection, indicating that the drug encapsulated by niosomes could effectively traverse the blood–brain barrier and reach brain cells. There was no significant difference in brain GB level between the borneol-containing and borneol-free complexes. The modification effects and addition methods of borneol require further investigation.

4 Conclusion

The optimal prescription of the GB–Pue niosomal composite drug was a hydration temperature of 60°C, a surfactant–cholesterol mass ratio of 1.5:1, a HLB of 10.5, and a drug–carrier mass ratio of 8:100. Pharmacokinetics and brain tissue distribution studies demonstrated that niosome technology, by encapsulating the drug in a bilayer, enables sustained release and penetration of the blood–brain barrier, extending its half-life and altering the drug distribution in human tissues and organs.

In the present study, pharmacokinetics and brain tissue distribution experiments showed that the prepared niosomal complex suspension had significant sustained release and improved blood–brain barrier penetration. The niosome technology and application of borneol enhanced the sustained release of the drug and its ability to traverse the blood–brain barrier, providing a foundation for the treatment of brain diseases, such as Parkinson’s and AD, with GB and Pue composite drugs. Nevertheless, the location of borneol modification and the enhancement of blood–brain barrier penetration require further exploration.

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Acknowledgments

This research work was financially supported by the National Natural Science Foundation of China (Grant No. 11975048) and the Beijing Union University Graduate Program.

  1. Conflict of interest: Authors declare no conflict of interest.

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Received: 2020-04-21
Revised: 2020-06-07
Accepted: 2020-07-28
Published Online: 2020-08-26

© 2020 Juntong Zhou et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/chem-2020-0089
Keywords for this article
ginkgolide B; puerarin; niosome; Parkinson’s disease
Creative Commons
BY 4.0

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
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  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
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  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
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  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
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  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
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  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
  48. Adsorption kinetic characteristics of molybdenum in yellow-brown soil in response to pH and phosphate
  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
  50. Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique
  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
  52. Cadmium (Cd) chloride affects the nutrient uptake and Cd-resistant bacterium reduces the adsorption of Cd in muskmelon plants
  53. Removal of H2S by vermicompost biofilter and analysis on bacterial community
  54. Structural cytotoxicity relationship of 2-phenoxy(thiomethyl)pyridotriazolopyrimidines: Quantum chemical calculations and statistical analysis
  55. A self-breaking supramolecular plugging system as lost circulation material in oilfield
  56. Synthesis, characterization, and pharmacological evaluation of thiourea derivatives
  57. Application of drug–metal ion interaction principle in conductometric determination of imatinib, sorafenib, gefitinib and bosutinib
  58. Synthesis and characterization of a novel chitosan-grafted-polyorthoethylaniline biocomposite and utilization for dye removal from water
  59. Optimisation of urine sample preparation for shotgun proteomics
  60. DFT investigations on arylsulphonyl pyrazole derivatives as potential ligands of selected kinases
  61. Treatment of Parkinson’s disease using focused ultrasound with GDNF retrovirus-loaded microbubbles to open the blood–brain barrier
  62. New derivatives of a natural nordentatin
  63. Fluorescence biomarkers of malignant melanoma detectable in urine
  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
  67. Design, synthesis and pharmacological profile of (−)-verbenone hydrazones
  68. Synthesis of magnesium carbonate hydrate from natural talc
  69. Stability-indicating HPLC-DAD assay for simultaneous quantification of hydrocortisone 21 acetate, dexamethasone, and fluocinolone acetonide in cosmetics
  70. A novel lactose biosensor based on electrochemically synthesized 3,4-ethylenedioxythiophene/thiophene (EDOT/Th) copolymer
  71. Citrullus colocynthis (L.) Schrad: Chemical characterization, scavenging and cytotoxic activities
  72. Development and validation of a high performance liquid chromatography/diode array detection method for estrogen determination: Application to residual analysis in meat products
  73. PCSK9 concentrations in different stages of subclinical atherosclerosis and their relationship with inflammation
  74. Development of trace analysis for alkyl methanesulfonates in the delgocitinib drug substance using GC-FID and liquid–liquid extraction with ionic liquid
  75. Electrochemical evaluation of the antioxidant capacity of natural compounds on glassy carbon electrode modified with guanine-, polythionine-, and nitrogen-doped graphene
  76. A Dy(iii)–organic framework as a fluorescent probe for highly selective detection of picric acid and treatment activity on human lung cancer cells
  77. A Zn(ii)–organic cage with semirigid ligand for solvent-free cyanosilylation and inhibitory effect on ovarian cancer cell migration and invasion ability via regulating mi-RNA16 expression
  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
  85. Antioxidant activity as a response to cadmium pollution in three durum wheat genotypes differing in salt-tolerance
  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
  87. Synthesis and efficacy of herbicidal ionic liquids with chlorsulfuron as the anion
  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
  114. Study on online soft sensor method of total sugar content in chlorotetracycline fermentation tank
  115. Studies on the Anti-Gouty Arthritis and Anti-hyperuricemia Properties of Astilbin in Animal Models
  116. Effects of organic fertilizer on water use, photosynthetic characteristics, and fruit quality of pear jujube in northern Shaanxi
  117. Characteristics of the root exudate release system of typical plants in plateau lakeside wetland under phosphorus stress conditions
  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
  122. Special issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  123. Insight into the cadmium and zinc binding potential of humic acids derived from composts by EEM spectra combined with PARAFAC analysis
  124. Source apportionment of soil contamination based on multivariate receptor and robust geostatistics in a typical rural–urban area, Wuhan city, middle China
  125. Special Issue on 13th JCC 2018
  126. The Role of H2C2O4 and Na2CO3 as Precipitating Agents on The Physichochemical Properties and Photocatalytic Activity of Bismuth Oxide
  127. Preparation of magnetite-silica–cetyltrimethylammonium for phenol removal based on adsolubilization
  128. Topical Issue on Agriculture
  129. Size-dependent growth kinetics of struvite crystals in wastewater with calcium ions
  130. The effect of silica-calcite sedimentary rock contained in the chicken broiler diet on the overall quality of chicken muscles
  131. Physicochemical properties of selected herbicidal products containing nicosulfuron as an active ingredient
  132. Lycopene in tomatoes and tomato products
  133. Fluorescence in the assessment of the share of a key component in the mixing of feed
  134. Sulfur application alleviates chromium stress in maize and wheat
  135. Effectiveness of removal of sulphur compounds from the air after 3 years of biofiltration with a mixture of compost soil, peat, coconut fibre and oak bark
  136. Special Issue on the 4th Green Chemistry 2018
  137. Study and fire test of banana fibre reinforced composites with flame retardance properties
  138. Special Issue on the International conference CosCI 2018
  139. Disintegration, In vitro Dissolution, and Drug Release Kinetics Profiles of k-Carrageenan-based Nutraceutical Hard-shell Capsules Containing Salicylamide
  140. Synthesis of amorphous aluminosilicate from impure Indonesian kaolin
  141. Special Issue on the International Conf on Science, Applied Science, Teaching and Education 2019
  142. Functionalization of Congo red dye as a light harvester on solar cell
  143. The effect of nitrite food preservatives added to se’i meat on the expression of wild-type p53 protein
  144. Biocompatibility and osteoconductivity of scaffold porous composite collagen–hydroxyapatite based coral for bone regeneration
  145. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  146. Effect of natural boron mineral use on the essential oil ratio and components of Musk Sage (Salvia sclarea L.)
  147. A theoretical and experimental study of the adsorptive removal of hexavalent chromium ions using graphene oxide as an adsorbent
  148. A study on the bacterial adhesion of Streptococcus mutans in various dental ceramics: In vitro study
  149. Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study
  150. Special Issue on Chemistry Today for Tomorrow 2019
  151. Diabetes mellitus type 2: Exploratory data analysis based on clinical reading
  152. Multivariate analysis for the classification of copper–lead and copper–zinc glasses
  153. Special Issue on Advances in Chemistry and Polymers
  154. The spatial and temporal distribution of cationic and anionic radicals in early embryo implantation
  155. Special Issue on 3rd IC3PE 2020
  156. Magnetic iron oxide/clay nanocomposites for adsorption and catalytic oxidation in water treatment applications
  157. Special Issue on IC3PE 2018/2019 Conference
  158. Exergy analysis of conventional and hydrothermal liquefaction–esterification processes of microalgae for biodiesel production
  159. Advancing biodiesel production from microalgae Spirulina sp. by a simultaneous extraction–transesterification process using palm oil as a co-solvent of methanol
  160. Topical Issue on Applications of Mathematics in Chemistry
  161. Omega and the related counting polynomials of some chemical structures
  162. M-polynomial and topological indices of zigzag edge coronoid fused by starphene
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