The purpose of this study is to investigate the bioavailability and glycaemic metabolism of cinnamon oil (CIO) carried by liquid-loadable tablets (CIO-LLTs), the carrier of a CIO self-emulsifying formulation (CIO-LS). The results of tests performed to evaluate the physical properties of the CIO-LLT complied with Chinese Pharmacopeia (2010). The release profile suggested that the CIO-LLT preserved the enhancement of in vitro dissolution of cio. After orally administration, the plasma concentration-time profile and pharmacokinetic parameters suggested that a significant increase (
According to the World Health Organization, it is estimated that approximately 150 million people worldwide have diabetes mellitus at present [
Cinnamon is one of the well-known and oldest spices, which has been used for centuries in several cultures [
However, SEDDSs are usually formulated in a liquid form which has some disadvantages such as high production costs, low drug incompatibility, and poor physical and chemical stability. The incorporation of the self-emulsifying mixture into a solid dosage form is desirable as it combines the advantages of SEDDS (high solubility and bioavailability) with those of solid dosage forms (high stability). The transformation of liquid lipid systems into a solid oral dosage form has been attempted by several methods such as capsule filling, spray drying, adsorption onto solid carriers, and melt granulation as well as other techniques [
Healthy male adult Wistar rats (2 months old and weighing
Cinnamon oil was obtained from Shanghai Yansheng biotechnology Co., Ltd. China. Magnesium aluminometasilicate (MAS) was obtained from Jinan Kailida Chemical Technology Co., Ltd China.
Based on the pilot studies, the blank SEDDSs were prepared by mixing of 30% Miglyol 812 (oil), 60% Cremophor RH40 and Tween 80 (surfactant, 2 : 1), and 10% Transcutol P (cosurfactant) at 50°C with a magnetic stirrer. Then CIO and Aerosil 200 (1000 mg) suspended in 150 mL ethanol were dissolved in the blank SEDDS with stirring until forming an isotropic mixture. The mixture was then kept at room temperature and equilibrating for 24 h.
The emulsification time of the SEDDS formulations was evaluated according to the way described in detail by Xi et al. [
Droplet size was determined by Zetasizer Nano ZS (Jinan Runzhi Instruments, China) with dynamic light scattering particle size analyzer at a wavelength of 635 nm and at a scattering angle of 90° at 25°C. All studies were repeated three times, and the values of
The composition of LLT was MAS/magnesium stearate (99.5 : 0.5 w/w%)[
Tablets were placed in excess of CIO-SEDDS and allowed to absorb the liquid until a constant tablet weight was reached. Before weighing, excess of liquid on the surface of the tablets was removed by tissue paper. After few hours of storage, the tablet surface is dry, comparable to the nonloaded tablet [
Tablets were evaluated by performing quality control tests for uniformity of drug content, friability, disintegration, hardness, and weight variation. All tests were carried out in triplicates and according to Chinese Pharmacopoeia (2010).
CIO-LS and CIO-LLT were tested in vitro in 950 mL purified water at 37°C using rotating basket apparatus (Chinese Pharmacopoeia) at a rotation speed of 100 rpm. Samples were withdrawn at predetermined time intervals and then mixed with 150
Wistar rats were divided randomly into four groups (six animals in each group). The first group (CIO) was treated orally (100 mg/kg) CIO formulated in normal saline containing 3% Tween 80. Group II (CIO-LS) and group III (CIO-LLT) were treated orally CIO-SEDDS (100 mg CIO/kg) and CIO-LLT (100 mg CIO/kg), respectively. Group IV was treated (i.v.) CIO sample (100 mg/kg) used as control group. Before dosing, the rats were fasted overnight. Food was given minimum 2 h after dosing. A 3 mL blood samples were drawn from the tail vein before dosing and at the following times: 15 min, 30 min, 45 min, 1 h, 1.5 h, 3 h, 4 h, 6 h, and 24 h after dosing. Blood samples were centrifuged at 3000 g for 10 min, and plasma samples were harvested. Each plasma sample (100
Pharmacokinetic parameters were calculated from the corresponding plasma concentration-time curves using noncompartmental analysis (WinNonlin 4.0, Pharsight, Mountain View, CA, USA). The area under the plasma concentration-time curve from time 0 to time infinity (AUC0–∞),
Animals were fasted for 12 h and were then injected (i.v.) with alloxan (75 mg/kg) solution that was made with saline. Forty-eight hours later, blood samples were collected from the tail veins of the rats. The blood glucose was analyzed with a Glucometer-4 (Bayer). The blood glucose level of rats greater than 11.1 mmol/L was selected as hyperglycemic rats.
Forty hyperglycemic rats were selected and randomly divided into 4 groups. The first group (CIO) was treated orally (100 mg/kg) CIO formulated in normal saline containing 3% Tween 80. Group II (CIO-LS) and group III (CIO-LLT) were treated orally CIO-SEDDS (100 mg CIO/kg) and CIO-LLT (100 mg CIO/kg), respectively. Group IV was treated orally saline used as control group. On the 45th day, blood samples were collected from the orbital veins to measure the to determine the blood glucose levels and HbA1c with the HbA1c Apparatus (Variant II, Bio-Rad Laboratories) and insulin with an enzyme-linked immunosorbant assay (ELISA) kit (Shanghai Jinma Biological Technology, Inc., China), respectively. Then, the rats were sacrificed. The pancreas was dissected out and placed in 10% buffered formalin and the liver was dissected out for the measurement of hepatic glycogen.
The data are expressed as mean ± SEM. Statistical significance was tested by two-tailed Student’s
The work presented in this paper focuses on the ability of LLT prepared from MAS to be loaded with a SEDDS system containing CIO, the pharmacokinetic (PK) performance of CIO from loaded LLT and the effects of CIO-loadable tablets (CIO-LLT) on glycaemic metabolism. MAS is nontoxic and consists of highly porous spherical particles with a median size of 110
SEDDS formulation disperse quickly and completely when subjected to aqueous environment under mild agitation. The efficiency of self-emulsification can be estimated by measuring the rate of emulsification and the droplet size distribution [
Reconstitution properties of the SEDDS.
SEDDS | |
---|---|
Emulsification time (seconds) | |
Zeta potential | |
Droplet size (nm) | 132.5 |
Polydispersity index (PDI) |
Values are shown as means ± SD.
It has been reported that any change in interfacial film influences the surface curvature of the droplet leading to differences in the droplet size [
A series of absorption experiments was conducted to explore the loading capacity of the LLT. Figure
Correlation between SEDDS loading and loading time.
Drug release profiles of the SEDDS and LLT.
Table
Characteristics of the CIO-loaded tablet.
CIO-loaded tablet | |
---|---|
Average CIO contents (% ± SD) | 96.11 ± 1.5 |
Friability (% ± SD) | |
Hardness (N ± SD) | 30.1 ± 7.00 |
Disintegration time (min ± SD) | |
Weight variation (mg) |
Drug release rate and the cumulative percent of CIO dissolved into the aqueous medium are important criteria that govern the quality of the LLT. The physical properties of the ingredients used to prepare the LLT have a profound effect on the CIO release rate. Drug release profiles of the CIO-tablet and CIO-SEDDS are shown in Figure
Figure
Pharmacokinetic parameters after oral administration of CIO, CIO-LS, and CIO-LLT to rats.
Groups | AUC0→24 h ( | |||
---|---|---|---|---|
CIO-LS | 1.96 | 2.5 | ||
CIO-LLT | 1.68 | 2.2 | ||
CIO | NA | NA | NA | 0 |
Values are shown as means ± SD. *
Mean whole blood concentrations of CIO in rats following oral doses of 100 mg in the form of CIO-SEDDS and CIO- LLT. The total plasma concentrations of drug after oral administration of CIO could not be detected.
A significant increase (
Alloxan is the most prominent diabetogenic chemicals in diabetes research. It is toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter [
The results of blood glucose from hyperglycemic rats induced by alloxan are presented in Table
Effect of CIO, CIO-LS and CIO-LLT on blood glucose and HbA1c levels in alloxan-hyperglycemic rats.
Different groups | Blood glucose (mmol/L) | HbA1c |
---|---|---|
Control group | ||
CIO-LS-treated | ||
CIO-LLT-treated | ||
CIO-treated |
Values are means ± SEM,
The mechanisms of the hypoglycaemic effect of CIO-LS and CIO-LLT have been also studied in this paper. As shown in Table
Effect of CIO, CIO-LS and CIO-LLT on serum insulin and hepatic glycogen level in alloxan-induced diabetic rats.
Different groups | Serum insulin ( | Hepatic glycogen (mg/g tissue) |
---|---|---|
Control group | ||
CIO-LS-treated | ||
CIO-LLT-treated | ||
CIO-treated |
Values are means ± SEM,
Islet cell death and replication represented by hematoxylin-eosin.
Glycogen storage in the liver is another way to maintain blood glucose concentration in mammals. Decreased hepatic glucose production is induced by glycogen synthesis. CIO-LS and CIO-LLT produced the increase in the level of hepatic glycogen. Concentrations of hepatic glycogen were lower in saline-treated rats than CIO-treated rats (Table
The work presented in this paper focuses on the ability of LLT prepared from MAS to be loaded with a SEDDS system containing CIO. It combines the advantages of SEDDS (high solubility and bioavailability) with those of solid dosage forms (high stability). CIO-loaded tablet could improve the glycaemic metabolism of CIO. It was contributed by improving the bioavailability drug by SEDDS.
This project was supported by Project of Shandong Province Higher Educational Science and Technology Program (J08LH62). Han, as the author of the manuscript, have or do not have a direct financial relation with the commercial identity mentioned in our paper that might lead to a conflict of interest for any of the authors.