Pharmacokinetic Study Of Polyvinylpyrrolidone PVP K12 In Rats

Pharmaceutical excipients are a class of auxiliary substances added to pharmaceutical preparations to improve the physicochemical properties or physiological characteristics of drugs.It plays a vital role in the stability and safety of drugs.With the development of formulation diversity,pharmaceutical excipients have evolved from simple excipients and additives to important components with multiple functions.Thereinto,pharmaceutical polymer excipients are widely used in sustained and controlled release preparations,temperature-sensitive hydrogel,nano drug delivery systems,targeted drug delivery systems due to their good biocompatibility.In addition to solubilizing,solubilizing,and improving the stability of drugs,it can also be used as a drug carrier to make a polymer carrier drug by physical embedding,chemical adsorption,and ion attraction.Being different from the traditional excipients,which can be cleared quickly in vivo,pharmaceutical polymer excipients need to be degraded slowly and may be exposed in vivo for a long time.In recent years,more and more studies have found that some previous recognized non-bioactive polymer excipients are not pharmacologically inert substances,existing certain potential safety risks,such as1)Tissue accumulation and potential organ toxicity of polymer excipients;2)Production of toxic metabolites;3)Interactions between the polymer excipients and cytochrome P450 enzymes or transporters in vivo,resulting in changes in the efficacy of loaded drugs or new toxic side effects.Hence,revealing the pharmacokinetic behavior of pharmaceutical polymer excipients is of great significance to the scientific design of pharmaceutical preparations and the evaluation of safety and effectiveness.Polyvinylpyrrolidone,as one of the three main synthetic polymer excipients,affects the pharmacokinetic properties of drugs in vivo closely and extensively.Thereinto,soluble polyvinylpyrrolidone PVP K12 is one of the main categories of polyvinylpyrrolidone,which is a linear homopolymer polymerized by N-vinyl-2-pyrrolidone?NVP?monomer.PVP K12 can be used as a cosolvent,stabilizer,film-forming agent,emulsifier and other auxiliary preparations.Besides,it can also be used as a carrier to encapsulate drugs to delivery and release drugs in vivo.However,there have been no recent reports on study of the interactions between PVP K12 and the body,whatsmore,the absorption,distribution,metabolism,and excretion of PVP K12 in vivo are not clarified.The lack of accurate quantitative analysis methods of polymer excipients in biological samples is the main reason for the slow progress of its fate in vivo research.Therefore,this subject established a quantitative analysis method of PVP K12 in vivo and made related pharmacokinetic studies.The specific contents are as follows:?1?Study on the charge of precursor ion of PVP K12 and its fragmentation pattern in mass spectrometry.This subject have analyzed the precursor ion distribution and charging rules of PVP K12 by the MS^ALL data acquisition of quadrupole time-of-flight mass spectrometry?Q-TOF MS?and the Q1 MS full scan of API 4000 triple quadrupole mass spectrometry.The chemical structural formula of PVP K12 is C₃H₇O-?C₆H₉NO?_n-H.Its parent ions are presented with[M+Na]⁺?[M+H]⁺and[M-H₂O+H]⁺in the mass spectrometry,and mainly present in the form of single charge.Besides,In Q-TOF MS,the precursor ion of PVP K12 mainly exists as[M+Na]⁺.In the ESI ion source of API 4000 triple quadrupole mass spectrometry,the precursor ion of PVP K12 mainly appears as[M+H]⁺.Besides,the fragmentation pattern of PVP K12 was studied,and stable specific fragment ions were found.The product ion fragments of PVP K12 present with the following two mathematical rules:97+?26?x+?111?y+?14?a+?60?b-?18?c+1 x,y=0,1,2,3…;a,b,c=0,197+?26?x+?111?y+?14?a+?60?b-?18?c+23 x,y=0,1,2,3…;a,b,c=0,1In mass spectrometry,certain collision energy and declustering voltage will not only break the C-C bond,but also break the C-N bond of the PVP K12.If C-N bond scissions happened,PVP-K12 will remove the pyrrolidone ring and rearrange to a form of an unsaturated double bond.?2?Establishment of quantitative analysis method of PVP K12 in rat plasma.An LC-MS/MS analysis method for PVP K12 in rat plasma was established by API4000 triple quadrupole mass spectrometry with multiple ion monitoring?MIM?scanning mode.Besides,the LC-MS/MS analysis method of biological samples was validated,including selectivity,calibration curve and linear range,accuracy,precision,matrix effect,extraction recovery,residue,stability,etc.The results proved that the method is accurate and reliable.?3?Pharmacokinetic study of PVP K12 in rat plasma.This subject made the pharmacokinetic study of PVP K12 in rat plasma.The results showed that after intravenous injection of 5 mg/kg PVP K12 in rats,PVP K12 was eliminated rapidly in rat blood,and the peak concentration C_maxax was 47.8±7.44?g/mL,the peak time T_maxax was 0.0167 h,the zero-time blood concentration C₀ was 60.0±11.0?g/mL.The elimination half-life t_1/2 is 0.536±0.0769 h,the area under the plasma concentration-time curve AUC_?0-t?is 14.5±3.12?g/mL·h,AUC_?0-??is 15.4±4.03?g/mL·h,the plasma clearance rate Cl is 0.324±0.07 L/h/kg,the apparent distribution volume V_z of PVP K12 is 0.251±0.0306 L/kg,and the steady-state distribution volume V_ss is 0.228±0.0133 L/kg.After administered the PVP K12,plasma's concentration was almost completely eliminated in 2.5 hours.In a nutshell,taking PVP K12 as the research object,this subject established a quantitative analysis method of in-source CID-MIM-LC-MS/MS in vivo,and applied it to the pharmacokinetic study of PVP K12 in rats.It breaks through the bottleneck of PVP K12 mass spectrometry quantitative analysis in vivo.It provides pharmacokinetic data support for the safety evaluation and quality evaluation of pharmaceutical excipients PVP K12 in drug design.