Abstract
Ziyuglycoside I (ZgI), a major effective ingredient of Sanguisorba officinalis L, has shown good activity in increasing leukocyte of myelosuppression mice. However, oral ZgI therapy has been deterred by poor bioavailability because of its low aqueous solubility and permeability. Our study was to develop ZgI-loaded self-microemulsifying drug delivery system (SMEDDS) and evaluate its intestinal absorption, and pharmacokinetic and pharmacodynamic activity for increasing leukocyte. The formulation was designed and optimized by measuring the equilibrium solubility of ZgI in different vehicles and the pseudoternary phase diagram. Further, morphology, particle size, stability, in vitro release, in situ single-pass intestinal perfusion (SPIP), in vivo activity, and in vivo pharmacokinetic (PK) of ZgI-SMEDDS were charactered or studied. Optimized formulations for in vitro dissolution were Obleique CC497, Tween-20, and Transcutol HP with a proportion of 0.25/0.45/0.30 via D-optimal mixture design. Results showed that the solubility of ZgI was enhanced up to 23.93 mg/g and its average particle size was 207.92 ± 2.13 nm. The release of ZgI had been greatly improved by the SMEDDS. In SPIP, the intestinal absorption of SMEDDS was much better than plain ZgI. In PK, we found the oral bioavailability of ZgI-SMEDDS was 6.94-fold higher absolute bioavailability (21.94 ± 4.67) % than ZgI (3.16 ± 0.89) %. The most important was that the mice WBC of ZgI-SMEDDS group was significantly higher than that of the ZgI group. Our study suggested that SMEDDS could increase the solubility of ZgI, which was beneficial to improve oral bioavailability and enhance biological activity.
Highlights
The bone marrow of cancer patients are severely damaged by multiple chemoradiotherapy or large doses of chemotherapy drugs, which usually lead to toxic effects[1,2], such as the myelosuppression which is the most frequent and serious one
Labrafil M 1944CS, Obleique CC497, Labrasol, and Transcutol P were purchased from France Jiafa Lions; medium-chain triglycerides (MCT) Mic acid ester, isopropyl myristate (IPM), oleic acid, ethyl oleate, and isopropyl palmitate (IPP) were purchased from Shanghai Chuxing Chemical Co., Ltd.; castor oil, Tween20, Tween-80, Tween-85, polyethylene glycol (PEG)-600,PEG-200, and PEG-400 were purchased from Chengdu Kelon Chemical Reagent Factory; and all other chemicals and reagents used were of HPLC grade
Our studies illustrated that self-microemulsifying drug delivery system (SMEDDS) containing Obleique CC497, Tween-20, and Transcutol HP with a ratio of 0.25/0.45/0.30 was showed to increase solubility and dissolution rate of Ziyuglycoside I (ZgI) and it may remain stable at least 3 months under limited conditions
Summary
The bone marrow of cancer patients are severely damaged by multiple chemoradiotherapy or large doses of chemotherapy drugs, which usually lead to toxic effects[1,2], such as the myelosuppression which is the most frequent and serious one. Protecting the bone marrow and increasing hemocyte (especially the WBC) counts of peripheral blood are very important for tumor patients to undergo chemoradiotherapy and improve their life quality. Our previous research showed that ZgI was the main active ingredient of Sanguisorba officinalis [4,5,6]. We intended to enhance the bioavailability and activity of ZgI for increasing WBC
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