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Back to Journal »International Journal of Nanomedicine» Volume 14

Synthesis and preliminary characterization of polyurethane nanoparticles with ginger extract as a cardiovascular protective agent

Author Borcan F, Chirita-Emandi A, Andreescu NI, Borcan LC, Albulescu RC, Puiu M, Tomescu MC 

Published on May 21, 2019, the 2019 volume: 14 pages 3691-3703

DOI https://doi.org/10.2147/IJN.S202049

Single anonymous peer review

Editor approved for publication: Dr. Thomas Webster

Florin Borcan,1 Adela Chirita-Emandi,2,3 Nicoleta Ioana Andreescu,2,3 Livia-Cristina Borcan,4 Ramona Carmen Albulescu,5 Maria Puiu,2,3 Mirela Cleopatra Tomescu4 1 First Department of School of Pharmacy (Analytical Chemistry), “Victor Babes” Medical University, Timisoara, Romania; 2 Second Department of Faculty of Medicine, “Victor Babes” Medical University, Timisoara, Romania (Genetics); 3 Genomic Medicine Center, “Victor Babes” Medical University, Romania Timisoara; 4 "Victor Babes" Medical University School of Medicine Fifth Department (Internal Medicine I), Timisoara, Romania; 5 11th Department (Pediatrics), "Victor Babes" Medical University, Timisoara, Romania Background and purpose: The ginger extract extracted from the rhizome of ginger contains 6-gingerol, 6-gingerol, 8-ginger oil and 10-ginger oil. It has many therapeutic effects, such as chemopreventive effects on stroke and heart disease, malabsorption, bacterial infections, indigestion and nausea, which have been observed since ancient times. The main purpose of this study is to evaluate polyurethane (PU) as a suitable material for preparing hollow nanoparticles. Method: PU nanoparticles are obtained by spontaneous emulsification, in the presence of non-ionic surfactants, combined with the interfacial polyaddition process between aliphatic diisocyanates and different mixtures of ether and ester polyols. No PU additives, such as catalysts, blowing agents, chain accelerators, crosslinkers and stabilizers are used in the synthesis process. Result: The particles exhibit an almost neutral pH and low water solubility. Their heat-resistant temperature is as high as 280°C. In a mouse skin test, the measurement of PU nanoparticles loaded with pure ginger extract (GE) found that the irritation level was lower than that recorded by pure GE. Conclusion: This study shows that the toxicity of these PU nanoparticles is reduced, so it is possible to use them as a cardiovascular protective agent. Keywords: CD1 Nu/Nu mice, drug carriers, hollow nanoparticles, toxicity, Zeta potential

Cardiovascular diseases are diseases of the heart and blood vessels, including coronary artery disease, cerebrovascular disease, or peripheral artery disease. 1 Cardiovascular disease is the leading cause of death in the world. Elevated cholesterol and triglyceride levels, increased fat percentage, and decreased muscle mass percentage cannot be offset by effective metabolism and regular physical activity. These are all favorable factors for cardiovascular disease. 2

Phytotherapy is a treatment method that uses medicinal plants to improve disease. This therapy has a history of a thousand years and has proven its effectiveness. Unlike allopathic drugs, which only recommend extracts from plants, phytotherapy uses plants as total extracts. From roots to flowers, including bark and flower buds, various parts of the plant (depending on the situation) are used together or individually. 3 The following main categories of plant compounds are used in different therapies: flavonoids (rutin, quercetin, epicatechin, kaempferol, etc.). ), phenolic acid (capsaicin, rosmarinic acid and tannic acid), hydroxycinnamic acid (coumarin and ferulic acid), organic sulfides (allicin, glutathione and sulforaphane), alkaloids (Theophylline and caffeine), carotenoids (β-carotene) and lycopene, anthocyanins, terpenes, isoflavones and phytosterols. 4 Vasanthi et al. described that some isoflavones, diosgenin, resveratrol, quercetin, catechins, sulforaphane, tocotrienols and carotenoids have been found to be reduced by their cardioprotective effects The risk of cardiovascular disease has anti-oxidation, anti-hypercholesterolemia, anti-angiogenesis, anti-ischemia, inhibition of platelet aggregation and anti-inflammatory activities. 5

Polyurethane (PU) material first appeared in the IG Farbenindustrie laboratory in Leverkusen 80 years ago; Professor O. Bayer obtained PU foam from toluene diisocyanate and polyester polyol. 6 The application of PU in the field of drug delivery is relatively new: Hong and Park developed the first PU microcarrier twenty years ago. 7 We have obtained PU nano and microstructures with different shapes and sizes in the past 5 years. 8-12 The purpose of this study is to obtain and characterize a mixture of polyester and polyether urethane, which can ensure the sustained release of pure ginger extract (GE) for a period of time. Long time.

The characteristics of the main commercially available reagents are shown in Table 1. The reagents are stored under the conditions specified by the manufacturer and can be used without further purification. Table 1 Main characteristics of reagents

Table 1 Main characteristics of reagents

Munteanu et al. described the procedure chosen to obtain GE; 10 Ginger root was crushed with a chisel, dried quickly at 90°C for 2 days, and then extracted with 70% ethanol for 24 hours. The resulting mixture was then filtered, centrifuged at 2,000 rpm at 25°C for 5 minutes, and concentrated to constant weight using a rotary evaporator at 90°C.

The procedure chosen for the synthesis is based on the interfacial polyaddition reaction combined with spontaneous emulsification (Figure 1); the scheme includes the following steps: 11,12 Preparation of the aqueous phase (PU soft segment) – BD, PEG and PCL, Tween® 20 The mixture of 0.5:1:1:30 and distilled water is heated at 35°C and homogenized in an Erlenmeyer flask (100 mL); the preparation of the organic phase (PU hard section)-the 1:15 mixture of LDI and acetone The mixture was heated at 35°C and homogenized in a Berzelius beaker (50 mL); the organic components were injected into the aqueous solution under magnetic stirring (400 rpm) and heated (35°C). PU nanoparticles began to appear as white precipitates at this moment. However, keep stirring at 40°C for 3 hours to ensure completion of all chemical reactions (maturation time); the obtained suspension is washed repeatedly with the mixture (acetone-water 3:1 v/v) to remove unwanted/by-products , Such as amine; the solvent and part of the water are removed by slow evaporation, and the suspension is kept as a thin layer at 50°C for about 72 hours. Figure 1 The chemical reaction used to synthesize polyurethane particles.

Figure 1 The chemical reaction used to synthesize polyurethane particles.

With different PEG/PCL ratios and with/without GE, the procedure described previously was repeated six times. Table 2 lists the main raw materials used in the two samples: sample PU_0 is a 1:1:1 (w/w) mixture of the first three synthetic products, and PU_1 combines the latter three synthetic products in the same ratio, because the Sample combinations with different polyether/polyester ratios will result in products containing particles with different degradation rates and ensure that the concentration of the drug released is approximately constant. Table 2 PU nanoparticles synthetic raw materials

Table 2 PU nanoparticles synthetic raw materials

The preliminary characterization of PU nanoparticles with and without GE starts with a series of dissolution tests. Follow the procedure described in ASTM D 3132-84.13, using distilled water, ethanol, acetone and DMSO as solvents

Use a portable pH Meter Checker® (Hanna Instruments, Woonsocket, RI, USA) and an aqueous solution with the same concentration (0.8 mg/mL) at the same temperature (25°C) to evaluate the pH value of the PU nanoparticle sample. The instrument was previously calibrated using four different buffer solutions (pH=3, 5, 7, and 10).

The MALDI-TOF technique is used to determine any changes in the chemical properties of nanoparticles after the addition of GE during the synthesis process. As the main component of GE, gingerol is a compound with two hydroxyl groups and can be used as a chain extender in the process of particle synthesis.

Bruker HCCA (α-cyano-4-hydroxycinnamic acid) matrix (5 mg/mL in a mixture of acetonitrile, water and trifluoroacetic acid) was used to suspend the nanoparticles. Add 1 µL of the suspension to the target plate (MTP 384 ground steel, Bruker Daltonics, Bremen, Germany). Allow the spots to dry at room temperature.

An UltrafleXtreme MALDI TOF/TOF instrument (Bruker Daltonics) was used to obtain mass spectra. Analyze in positive ion reflection mode in the mass range of 700–3,500 m/z. The instrument was calibrated using Brukertide Calibration Standard I, which contains a mixture of seven standard peptides. Flex Control® (version 3.4) software is used to collect data and set method parameters. The following settings were used: laser frequency-1,000 Hz; smartbeam-"4_large"; sampling rate and digitizer settings-2.50 GS/s; accelerator voltage-20.12 kW; extraction voltage-17.89 kW; lens voltage-7.23 kW; delayed extraction – 120 ns; and reflector voltage – 20.23 kW. Adjust the laser intensity so that the highest peak in the spectrum is within 104 arbitrary units. Each individual spectrum uses 1,000 laser shots, and at least 10 individual spectra (10,000 laser shots) are accumulated and stored.

The mass spectra were processed using Flex Analysis® software (version 3.4, Bruker Daltonics).

Bouchemal et al. describe a procedure for evaluating the amount of active agent encapsulated in PU nanocapsules; the protocol is based on using UV-Vis absorption related to the amount of the drug added to the synthesis to determine free/untrapped drug. 14

The formula is: Encapsulation rate = (1-Number of free drugs/Number of added drugs)⨰100.

The thermal behavior of samples containing PU nanoparticles was studied by differential scanning calorimetry (DSC). Place a small sample of 3.4 to 3.7 mg in an aluminum crucible with a perforated lid and heat it to 30°C to 280°C in an inert atmosphere (use an Ar flow rate of 100 mL/min to prevent samples during DSC operation Pollution and oxidation), the heating rate is equal to 5 degrees per minute. A reference material (empty aluminum crucible with perforated lid) undergoes the same procedure at the same time. The instrument is DSC1 (Mettler-Toledo, Greifensee, Switzerland), previously calibrated using Zn and In as standards.

The Cordouan Zetasizer (Cordouan Technologies, Pessac, France) was used to evaluate the size and surface charge of PU nanoparticles with and without GE. The instrument contains two different analyzers: Vasco particle size analyzer and Wallis Zetapotential analyzer. Vasco Analyzer sets the following parameters: working temperature (25°C); time interval (22 μs); number of channels (410±20); laser power (80±5%); acquisition mode (continuous) and analysis mode (Pade-Laplace ). In the case of Wallis Zetapotential Analyzer (Cordouan Technologies, Pessac, France), the parameters are: suitable for plastic cuvettes between 380 and 780 nm; temperature (25°C); laser power (75±5%); application Field (automatic); resolution (0.8 Hz-medium); 3 bars/sequence, and Henry's function (Smoluchowski).

Use PVDF (polyvinylidene fluoride) artificial membrane Spectra/Por®: 15 Put 2.0 ml of sample into the dialysis tube, and use 100 ml of saline buffer in the outer chamber to test polymer nanoparticles with and without GE Permeability through the membrane. The experiment was carried out at room temperature. Every 10 hours, 1.0 mL of liquid from the outer chamber was replaced with fresh buffer, and the absorbance recorded at 290 nm was analyzed by comparing UVi Line 9400 (SI Analytics, Mainz, Germany).

Twelve CD1 Nu/Nu, 2 months old, female mice were purchased from Charles River (Budapest, Hungary), divided into 4 groups: group B (mouse blank, solvent treatment), PU_0 group (mouse PU nanoparticle solution Treatment), PU_1 group (mice treated with GE-loaded particle solution) and G group (mice treated with pure GE).

Apply the solution to the back skin every three days (0.5 ml/time), and measure the skin parameters within 20 minutes after each application. All measurements were performed in accordance with the published guideline 16, using the multi-probe adapter system (MPA5) of Courage&Khazaka Electronics, Germany, equipped with Tewameter® TM300 probe and Mexameter® MX18 probe, performed by the same operator at the same time of the day, in a narrow range Temperature (22±1 °C) and air humidity (40±3%).

Human and animal skins play a vital role in protecting the body from different pathogens. 17 The Tewameter® TM300 probe is designed to evaluate the barrier function of the skin. Transdermal Water Loss (TWL) is a natural process, and its important increase indicates the breakdown of the skin barrier (wounds, scratches, burns, exposure to solvents or surfactants, and extreme dryness), and it is reported to be a good predictor of irritation The parameters give the potential of the compound. 18

On the other hand, mexametry is a technique used to determine the two components of skin color: melanin and hemoglobin (erythema). 19 The Mexameter® MX18 probe emits green, red and infrared rays, and it only takes 1-3 seconds to calculate the amount of light absorbed by the skin.

All statistical analysis is performed using the trial version of IBM SPSS. The measurements of this study were performed in triplicate, and the results are expressed as the mean ± SE. Use one-way analysis of variance and Bonferonni-Dunn test to determine the statistical difference between the experimental group and the blank group; *, **, and *** indicate p<0.05, p<0.01, and p<0.001.

All investigations were conducted in accordance with the Helsinki Declaration of Principles. The author declares that all procedures involving animal subjects comply with specific regulations and standards: this study was first evaluated and approved by the "Victor Babes" ethics committee of the University of Medicine and Pharmacy of Timisoara, Romania. The working protocol follows the rules of the National Institute of Animal Health: During the experiment, the animals are kept under standard conditions of 12 hours of light and dark cycles, food and water at random, at 25±1°C and humidity >55%.

The stability of the samples was first monitored after synthesis in a similar manner as described by Borcan et al.: 11 After purification, a part of each sample was separated, separated and kept at 3 different temperatures (8±0.1°C, Refrigerator, 25±0.1 and 40±0.1 in a laboratory incubator) for 30 days. During this period, all aspects including the color of the sample remained stable.

Table 3 shows the pH and solubility values ​​of samples containing PU particles (PU_0 and PU_1). An increase in the solubility values ​​of PU samples containing GE in water, ethanol, and acetone was observed, which may be because the PU chains may have different numbers of free hydroxyl groups, depending on the drug embedded. Table 3 pH value and solubility of samples in different solvents

Table 3 pH value and solubility of samples in different solvents

The main component (PEG) of our synthesis can be observed on the MALDI-TOF MS spectrum (Figure 2). The two samples (PU_0 and PU_1) showed similar spectra with an average m/z of 1,420. In the two samples, the strongest peak was observed at 1,199 m/z. The masses of adjacent peaks differ by one monomer unit (average value is 44.5 m/z). No significant differences were observed between the two samples, so when the extract was loaded, no changes were detected in the particle chemistry. Figure 2 MALDI-TOF spectrum of polyurethane particles.

Figure 2 MALDI-TOF spectrum of polyurethane particles.

Ketata et al. described in their paper that PU fragmentation is similar to thermal decomposition; the recasting of raw materials (polyols and diisocyanates) is the main pathway of these degradation processes. 20

The PU sample has a maximum absorbance between 300 and 310 nm, while GE exhibits a peak at 386 nm (Figure 3). This wavelength was chosen to evaluate the amount of free active substances; four solutions of different concentrations were prepared, and absorbance and calibration curves were drawn (R2=0.997). By reporting the amount of free drug and the amount of all GE added to the synthesis, an encapsulation efficiency equal to 82.9% is obtained. Figure 3 UV-Vis spectra of polyurethane particles and ginger extract.

Figure 3 UV-Vis spectra of polyurethane particles and ginger extract.

The DSC curve shows that the melting point and boiling point (endothermic phase change), crystallization (exothermic process) and other material parameters of the unknown sample, such as the glass transition of the polymer, etc., 21 PU nanoparticles are a stable temperature range within the research range. Bolcu et al. have described that the decomposition of PU starts at about 300±20°C, depending on the aliphatic/aromatic characteristics of the diisocyanate radicals. 22 No significant differences were observed between the samples with and without GE (Figure 4). Figure 4 DSC thermogram of a polyurethane sample. Abbreviations: DSC, differential scanning calorimetry; PU, polyurethane; PU_0, polyurethane sample without ginger extract; PU_1, polyurethane sample with ginger extract; laboratory, laboratory; UMFT, Timisoara Medicine University; foreign, foreign language.

Figure 4 DSC thermogram of a polyurethane sample. Abbreviations: DSC, differential scanning calorimetry; PU, polyurethane; PU_0, polyurethane sample without ginger extract; PU_1, polyurethane sample with ginger extract; laboratory, laboratory; UMFT, Timisoara Medicine University; foreign, foreign language.

Table 4 shows the size and surface charge values ​​of PU nanoparticles without and with GE (PU_0 and PU_1). Table 4 Zetasizer characterization of synthetic samples

Table 4 Zetasizer characterization of synthetic samples

Munteanu et al. have proposed that colloidal suspensions with zeta potentials> 30 mV are exceptionally stable, while particles with zeta potentials between 20 and 30 mV have a moderate tendency to form clusters to increase their stability. 10 The particle size is <100 nanometers; therefore, it can be understood that the carrier contains nanoparticles.

Nanoparticles play an important role in modern medicine due to their fluidity, chemical reactivity and increased energy absorption. Murthy has written about quantum dots and their applications in optical imaging, superparamagnetic iron oxide nanoparticles in magnetic resonance imaging, and polymer and liposome-based nanoparticles for drug and gene delivery. twenty three

Their increased fluidity allows passage through different membranes. However, transport across membranes is limited by their size, shape, and surface characteristics. The membrane permeability was evaluated using the dialysis program and the change in GE concentration was calculated at 386 nm using Beer-Lambert's law (Figure 5). Figure 5 The evolution of the amount of ginger extract passing through the membrane.

Figure 5 The evolution of the amount of ginger extract passing through the membrane.

The degradation of PU nanoparticles was delayed by 2 days, and the maximum concentration of GE was obtained through artificial membranes after 3-4 days. This situation often occurs when PEGylated particles are used as drug carriers; polyether-based particles exhibit delayed degradation due to their increased stability against hydrolysis.

The skin is a sensitive organ and its parameters will be modified in different experiments. Skin tissue varies from person to person, depending on life experience, work, and daily personal care. Stimulants such as strong acidic compounds or alkalis can change important skin parameters, such as transdermal dehydration, erythema, and the hydration level of the stratum corneum. Figure 6 shows the evolution of TWL. Figure 6 The evolution of TWL during the experiment.

Figure 6 The evolution of TWL during the experiment.

In the skin evaluation, the TWL of pure GE increased significantly during the 3-week experiment, and this increase may be related to irritation. It is well known that hot pepper skin patches can relieve rheumatic pain. On the other hand, the stimulating properties of spicy herbs are also well known. In the case of encapsulating GE in PU nanoparticles, the evolution of TWL shows a lower growth; therefore, we can understand that this carrier is suitable due to its lower stimulating effect.

Skin pigmentation mainly depends on the level of melanin. Fitzpatrick Skin Phototype I people always burn their skin instead of tanning, while people with Phototype V and VI always get tanned. The 24 CD1 Nu/Nu mouse strain has white and sensitive skin; this is why a small increase in melanin index was obtained in our experiment. The melanin scale used by Courage-Khazaka has 1000 arbitrary units; therefore, our change (approximately 70 units/3 weeks) is insignificant (Figure 7). Figure 7 The evolution of melanin during the experiment.

Figure 7 The evolution of melanin during the experiment.

Erythema, perhaps the most important skin parameter, is another skin parameter evaluated in our experiments. Figure 8 shows an important increase in hemoglobin levels in the case of mice treated with GE. This increase confirms the skin changes implied by the increase in TWL. Other samples, with and without GE PU nanoparticles, showed similar increases as the blank. Figure 8 The evolution of erythema during the experiment.

Figure 8 The evolution of erythema during the experiment.

Nanotechnology at this moment is regarded as a kind of "emerging technology" that can completely change many fields. In pharmaceutical technology, the main priority of research is to develop alternative routes of administration. 25 The emergence of nano-drugs and drug delivery systems, especially polymer carriers, is related to advances in understanding disease mechanisms and the development of new drugs. The polymer structure and synthesis method are adapted to its physical and chemical properties. Although drug delivery systems based on synthetic polymers have been used for drug delivery in recent decades, there are still several examples of the use of new macromolecules in this field. It is important to explore these macromolecules and persist in studying their production methods, which are cleaner, more efficient, and less costly, although their clinical approval can be laborious. Nevertheless, their clinical approval can be difficult. 26

GE is often used because of its rich volatile oil components. In traditional Chinese, Indian and Japanese medicine, it is used to increase digestion due to the effect of heating, for abdominal distension, nausea, vomiting, and respiratory diseases characterized by increased coldness. In Africa, this plant was introduced in the 15th century and used by locals to treat malaria and yellow fever. In the 13th century, Dr. Rhiwallow wrote the first ginger-based medical treatment on the order of the Prince of South Wales. At present, ginger is grown in tropical countries all over the world. 27,28

Verma et al. described that dried ginger powder has an important protective effect on cardiovascular diseases, by reducing lipid peroxidation and enhancing the fibrinolytic activity of experimentally induced rabbit atherosclerosis. 29 Only 1 g of ginger powder is used to treat platelet aggregation in patients with p-nifedipine and antihypertensive. The dose of 10 grams of powder can significantly reduce platelet aggregation in patients with coronary artery disease. 30,31 On the other hand, scientific literature shows that the natural compounds in ginger are beneficial for blood pressure and they help reduce elevated blood sugar levels and blood lipid concentrations. 32-37

Ethanol extract suppresses weight gain and reduces insulin and serum glucose levels caused by a fat diet. 38 Unfortunately, due to the synergistic effect of alcohol and its compounds, this extract is contraindicated in gastritis and gastroduodenal ulcers. Encapsulating GE in a drug delivery system with controlled release is the solution to this problem.

The molecular weight of the polymer always presents a distribution with different degrees of dispersion. The polydispersity index (PDI) value is the ratio of the weight average molecular weight (Mw) to the number average molecular weight (Mn). 39 Mn depends on the quality of PEG used as a raw material, and the dependence is almost linear; Ketata et al. found that the Mn of PU synthesized from PEG 200 is 230 through ESI/MALDI-TOF technology, while the Mn of PU based on PEG 2000 is 230. For 2,030.40, different PU nanoparticles have been obtained in this study to ensure extended release of GE; PDI between 0.4 and 0.7 indicates that a carrier with an increased degree of heterogeneity is obtained.

The encapsulation rate of the drug carrier is an important feature. The drug loading depends on the size of the carrier particles. On the other hand, Biswal et al. studied the effect of drug/polymer ratio on encapsulation efficiency. 41 They found that a ratio of 1:1 and 1:2 resulted in a moderate encapsulation efficiency (between 54% and 68%), while a ratio of 1:5 and 1:6 resulted in the best encapsulation efficiency (about 95%). Compared with other polymer carriers (such as dendrimers), Hallow PU nanoparticles always show higher encapsulation efficiency; we obtained a satisfactory encapsulation efficiency in this study, reaching 82.9%.

The evaluation of TWL and erythema showed the non-irritating effect of GE samples embedded in PU nanoparticles.

In this experiment, the addition polymerization process combined with simultaneous emulsification was used to obtain PU nanoparticles with GE. The product has an almost neutral pH value and low solubility, and is stable to thermal degradation. The transmembrane carrier contains particles approximately 90 nm in size, which are moderately stable and do not form clusters; they absorb at 300–310 nm. A good encapsulation efficiency (82.9%) and transmembrane permeability were obtained. In in vivo tests on mouse skin, the carrier with and without GE showed no irritation.

The MALDI-TOF analysis was performed at the Genomic Medicine Center of the "Victor Babes" Medical University in Timisoara, Romania (POSCCE [Programul Operational, code SMIS [Sistemul Unic de Management al Informației pentru Instrumentele Structurale (Unique Information Management System for Structural Instruments) ): 48749, "Genomics Medicine Center v2", contract 677/09.04.2015).

The authors report no conflicts of interest in this work.

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