BACKGROUNDThe thermo-sensitive in situ gels based on copolymers are attractive as an injectable drug delivery carriers for sustained releasing of hydrophilic drugs. The purposes of this work are to investigate the release behavior in vitro and pharmacokinetic profiles in vivo of peptide and lowmolecular- weight hydrophilic drug loaded in the in situ gels.METHODSA triblock copolymer PLGA-PEG-PLGA (1402-1000-1402) 1115A (1115A) was synthesized and its rheological and gelatin properties were evaluated. The temperature-sensitive in situ gels based on 1115A of LXT-101, a polypeptide drug, were prepared and the release characteristics in vitro and pharmacokinetic behavior in vivo were investigated. Meanwhile, naltrexone hydrochloride (NTX), a water-soluble low-molecular-weight drug was chosen as the model drug and the in situ gels were also prepared and studied comparatively.RESULTSSlow-release characteristics were observed in vitro with in situ gels of LXT-101 and NTX. The release profiles and the mechanisms were different manifested by that NTX was released from in situ gels faster and more completely than LXT-101. Otherwise, the release pattern of LXT-101 showed a biphasic mechanism, an initial Fickian diffusion followed by a combination of degradation and diffusion at a later stage. The results of pharmacokinetic study indicated that a sustained release behavior could be obtained with MRT0-t (30.34 ± 12.47) h for LXT-101 and MRT0-t (2.37 ± 0.876) h for NTX, about 10 and 4 times longer than those of aqueous solution respectively. The pharmacodynamics studies in vivo further showed that in situ gel formulations of LXT-101 could sustain efficacy 6 days compared with only 1 day for aqueous solutions.CONCLUSIONThe results of release behavior in vitro and in vivo indicated that in situ gels with copolymer 1115A could be served as carriers for delay-released drug delivery systems and might be more suitable for polypeptide drugs compared to low-molecular-weight hydrophilic drugs.

12 Jan 2015·Current Pharmaceutical BiotechnologyQ4 · MEDICINE

Oil-based Formulation as a Sustained-Released Injection for a Novel Synthetic Peptide

Q4 · MEDICINE

Article

Author: Zhang, Guiying ; Li, Jinglai ; Quan, Dongqin ; Gao, Lijun ; Wang, Tao

In this study, sustained-release of GnRH antagonist peptide LXT-101 was realized through oil formulation, and their releasing characteristics in vitro and in vivo were investigated. In this formulation, the static interaction between cationic charged peptide LXT-101 and the negative charged phospholipid led to the formation of the phospholipid-peptide complex, by which LXT-101 was completely dissolved in oils. This formulation was prepared by mixing an aqueous solution of LXT-101 and empty SUV (small unilamellar liposomes) containing EPC (phosphatidylcholine) and DPPG (1, 2-dipalmitog-sn-glycero-3- phosphoglycerol) at an appropriate ratio, the mixture was subsequently lyophilized, and the resultant was dissolved in the oil to form a clear oily solution containing solubilized peptide LXT-101. With atomic force microscopy combined with Langmuir-Blodgett technology, the morphology of the particles in the oily solution were examined to be oval-shaped and the mean particle size was 150 nm in diameter. In pure water at 37°C, about 70~90 % of LXT-101 was released slowly from the oily formulation over 7 days. An effective sustained suppression of testosterone in beagle dogs could be achieved over a period of seven days with this LXT-101 oily formulation, by i.m. at a dose of 0.2 mg/kg (2 mg/ml). This formulation dramatically improved the bioactivity of LXT-101 compared to its aqueous solution. It was also found that when the concentration of peptide LXT-101 was up to or over 10 mg/ml in aqueous solution, there was no significant difference between the oily formulation and aqueous solution. This fact meant that LXT-101 itself could conduct sustained release in vivo by self-assembly of nanofibers.

01 Aug 2014·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Morphology of nanostructures and their long-acting properties in vivo for a novel synthetic peptide of gonadotropin-releasing hormone antagonist

Q3 · MEDICINE

Article

Author: Zhang, Guiying ; Li, Jinglai ; Wang, Tao ; Quan, Dongqin ; Gao, Lijun

AbstractObjectivesTo demonstrate the correlation between the nanostructure formation and the long duration of action in vivo of peptides, the morphology of nanostructures of LXT-101, a novel synthetic amphiphilic peptide of gonadotropin-releasing hormone antagonist were observed when dissolved in different solvents, and their long-acting properties in vivo were investigated in this study.MethodsThe morphology of nanostructures of LXT-101 was observed by transmission electron microscopy when dissolved in different solvents, and the plasma concentrations of LXT-101 and testosterone levels were also assayed for different solutions after intramuscular injection administration in beagle dogs.Key findingsTEM data suggest that LXT-101 in pure water can form fibres, while in mannitol, dextrose or sodium chloride solution, they tend to form vesicles. The pharmacokinetic and pharmacodynamic results showed that the plasma concentrations of LXT-101 within 48 h were much higher but descended dramatically with mannitol, dextrose and NaCl solutions structurally composed of vesicles compared with that of pure water structurally composed of fibres. An effectively suppression of testosterone can be achieved only 2 or 3 days with the frontal three solutions, while LXT-101 in pure water maintained over a period of 7 days.ConclusionsIt may indicate that LXT-101 peptide in pure water forms fibre depot that release monomeric active peptide slowly. The correlation between the nanostructure and duration of action in vivo suggests that the addition of excipients influence self-assembly process of LXT-101 that leads to the formation of different nanostructures and exhibit various behaviours in vivo.

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Indication	Highest Phase	Country/Location	Organization	Date
Prostatic Cancer	Discovery	CN	Beijing Institute of Pharmacology and Toxicology	-

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