| Purpose:Paclitaxel has become a first-line drug in the treatment of a variety of malignant tumor diseases due to its broad spectrum and effective anticancer effects,which has attracted widespread attention.However,due to the poor solubility of paclitaxel itself,it is difficult to develop paclitaxel preparations,so currently the preparations on the market are usually injections.But paclitaxel injection still has many drawbacks.Taxol?is prone to strong hypersensitivity reaction due to the use of solvation-enhancing Cremophor-EL,which requires pre-treatment of anti-allergy drugs and long-term injection.Although Cremophor-EL is no longer used for the new generation of paclitaxel injection,clinical administration of Lipusu?must use a dedicated generator and still require anti-sensitization pretreatment.Abraxane?,an albumin-bound paclitaxel,is expensive and adds additional financial burden to patients.In addition to poor patient compliance,the above injections still have safety problems in terms of dose-limiting toxic reactions（neutropenia,neuropathic pain）.Compared with injections,paclitaxel oral preparation is safer and more convenient,but it needs to overcome the effects of P-gp efflux and first-pass effect while solving the solubilization problem,which increases the difficulty in the research and development of oral preparation.Only capsule Oraxol and solution DHP 107are in the clinical trial stage in China.Efficacy or safety（neutropenia and gastrointestinal adverse reactions）need to be improved.Therefore,the development of a more safe,efficient,stable and economical novel paclitaxel delivery system has broad prospects and great significance.Aiming at the problems and defects of existing paclitaxel preparations,our research team has been committed to the research and development of new paclitaxel delivery systems for a long time.Three novel paclitaxel delivery systems with great development potential have been established,among which GPL 116 is the delivery system for injection,YLP 214 and LPL 616 are the delivery systems for oral use.However,the characteristics of their pharmaceutical behavior are not clear,and the occurrence of dose-limiting toxic reactions is unknown.Therefore,this study conducted a preliminary study on the pharmaceutical characteristics and safety of the three paclitaxel delivery systems,to explore the respective advantages of the three,and to provide a strong basis for further research and development of paclitaxel delivery systems in the future.Methods:1.Study on basic characteristics of three novel paclitaxel delivery systemsDynamic light scattering（DLS）,differential scanning calorimetry（DSC）and Fourier infrared scanning（FIR）were used to characterize the three systems.Then,the hemolysis and coagulation tests and stability tests under different p H conditions were conducted to study the system’s hemolysis in vitro and the stability of the system under simulated physiological p H conditions in vitro.2.In vivo pharmacological behavior of three novel paclitaxel delivery systemsThe pharmacokinetic and tissue distribution tests of KM mice and SD rats were conducted to study the drug delivery characteristics of injection delivery system Taxol?and GPL 116 after caudal intravenous administration.The pharmacokinetic and tissue distribution tests of KM mice were also conducted to preliminarily explore the pharmaceutical behavior characteristics of oral delivery systems YLP 214 and LPL616.The area under the curve（AUC）of plasma and tissue was calculated for comparative evaluation.To evaluate the feasibility of intraperitoneal administration of GPL 116,Taxol?and Nab-PTX in ovarian tissue,the distribution characteristics of them were also investigated.3.Preliminary comparative study on the absorption mechanism of oral paclitaxel delivery systemsIn vivo gastric perfusion,in vivo intestinal perfusion,colon ectropion and lymphatic inhibition were studied,and the absorption percentage P%and apparent permeability coefficient PAPP were calculated.The gastrointestinal absorption characteristics of YLP214 and LPL 616 systems were preliminarily investigated.4.Preliminary study on adverse reactions of three novel paclitaxel delivery systemsTaking the occurrence of dose-limiting toxicity（neuropathy pain and neutropenia）as the safety evaluation object,is happening as safety evaluation objects.The changes of thermal withdrawal latency（TWL）in different paclitaxel delivery systems were determined by hot-plate procedure,and the number of WBC and Gran#and other blood routine indexes were determined.The dose-limiting toxicity of three novel paclitaxel delivery systems（GPL 116,YLP 214 and LPL 616）and marketed formulations(Taxol?and Nab-PTX)were evaluated.Results:1.The results of basic properties in vitro showed that GPL 116,YLP 214 and LPL616 were clear and translucent liquids with good fluidity at room temperature;The particle sizes were 18.25±0.06nm,25.25±0.186nm and 23.50±0.157nm,respectively.The results of DSC and FTIR showed that paclitaxel existed in an amorphous state in all three delivery systems.Taxol?,Nab-PTX and GLP116 all met the pharmacopoeia requirements without significant hemolysis and coagulation.The paclitaxel leakage rates of the API,YLP 214 and LPL 116 were 92.9%,10.5%and 6.1%in the highly acidic environment at p H 1.2,and 88.65%,8.6%and 17.8%in the environment at p H 4.5,respectively.In the p H 6.8 environment,they were 96.6%,13.4%and 8.9%,respectively,and in the p H 7.4environment,they were 90.6%,7.9%and 4.5%,respectively,indicating that most drugs for oral paclitaxel delivery system were tightly encapsulated in the corresponding gastrointestinal environment and had good stability.2.Pharmacokinetic study results in mice showed that:the paclitaxel delivery system GPL 116 and the marketed formulation Taxol?after a single dose through the tail vein,the drug time curve of GPL116 was similar to that of Taxol?.The half-life(t1/2)was 0.60h and 0.69 h,the clearance rate values（CL）was 0.86 and 0.74,the plasma AUC was11.61μg*h/m L and 13.45μg*h/m L,respectively.GPL 116 had a faster plasma clearance,a shorter half-life,and a lower plasma AUC,suggesting a lower plasma exposure.The peak times of oral paclitaxel delivery system YLP 214 and LPL 616 were 2.00 h and 0.50h,the half-lives were 1.56 h and 1.45 h,the clearance rate values were 2.32 and 3.12,and the plasma AUC were 21.56μg*h/m L and 16.04μg*h/m L,respectively.The oral absolute bioavailability of them were 32%and 24%,respectively,which was higher than DHP 107（23%）developed by Dahua Pharmaceutical in Korea.3.The results of tissue distribution in mice showed that the paclitaxel delivery system GPL 116 and the marketed formulation Taxol?after t a single dose through the tail vein,the AUC（0-12h）in the lung of mice were 64.88μg*h/m L and 31.67μg*h/m L,GPL 116 was 2.05 times of Taxol?,and had better lung tissue distribution advantage.The AUC（0-12h）in ovarian tissue of GPL 116 and Taxol?were 24.53μg*h/m L and 21.21μg*h/m L respectively,GPL 116 was similar to that of Taxol?.The distribution of AUC in ovarian and lung of rats was the same as that in mice.The AUC of oral paclitaxel delivery system YLP 214 in lung,ovary and stomach tissues were 257.98μg*h/m L,655.49μg*h/m L and 352.69μg*h/m L,respectively.The AUC of LPL 616 in the three tissues was 301.78μg*h/m L,386.56μg*h/m L and 1160.44μg*h/m L,indicating that the distribution of YLP 214 was more concentrated in the lung and ovarian tissues,while the distribution of LPL 616 was more concentrated in the lung and stomach.Compared with DHP 107 from Daehwa Pharmaceuticals,both YLP 214 and LPL 616 increased the distribution and accumulation in lung and ovary.The AUC of lung were 3.72 and 4.35times of DHP 107,respectively,and the AUC of ovary were 8.91 and 5.26 times of DHP107,respectively.At the same time,the AUC of LPL 616 in stomach was 1.88 times of that of DHP 107,manifesting a significant advantage.Taxol?,Nab-PTX and GLP116 were given in a single dose intraperitoneally in mice,the Cmax of Taxol?and GPL 116 in ovarian tissue were increased by 1.38 times and 2.27times compared with that of intravenous administration.The drug could still be detected at 24 h（only 6 h after caudal intravenous injection）.The AUC of Taxol?、Nab-PTX and GPL 116 in ovarian tissue were 207.39μg*h/m L,228.32μg*h/m L and 194.57μg*h/m L,respectively.The AUC in ovary of Nab-PTX and GPL 116 was 110.09%and 93.82%of Taxol?,respectively,indicating the cumulative distribution of ovarian tissue was similar for the three groups after intraperitoneal administration.4.A preliminary comparative study on the absorption mechanism of the oral paclitaxel delivery system showed that:The gastric absorption of the two oral delivery systems was significantly enhanced.When the concentration of the solution was 300μg/m L,the gastric absorption rates of the API,YLP 214 and LPL 616 were 9.18%,31.17%and 62.21%,respectively.The gastric absorption rates of the two oral delivery systems were 3.4 times and 6.8 times of those of PTX API,respectively.The gastric absorption rate of LPL616 was 2.0 times that of YLP 214,which may be the reason for the greater distribution of LPL 616 in the stomach.It also increased absorption in the intestine,especially the ileum and colon.The absorption rate Ka of YLP 214 in ileum and colon was 2.48 times and 3.75 times that of PTX API,respectively.The absorption rate（Ka）of LPL616 in intestinal segments was 3.85 times and 5.54 times that of PTX API,respectively.The apparent permeability coefficient（Papp%）of YLP 214 in duodenum and colon was 8.56 times and 6.63 times as that of PTX API,respectively.The Papp%of LPL 616 in ileum and colon was 2.35 times and 4.33 times as that of PTX API.The absorption rates（P%）of YLP 214 and LPL 616 in colon were 3.75 times and 2.42 times of PTX API,respectively.The promotion of overall gastrointestinal absorption led to a significant increase in oral bioavailability of YLP 214 and LPL 616.Colon valgus test showed that YLP 214 and LPL 616 had similar effects of promoting colonic absorption as P-gp inhibitors.After lymphatic inhibition,plasma AUC of PTX API,YLP 214 and LPL 616 decreased by 34.08%,79.28%and 38.64%,respectively.These results suggested that the oral bioavailability of YLP 214 and LPL 616 systems was related to the lymphatic transport mechanism.5.The preliminary safety evaluation results show that:For neuropathic pain,pain thresholds in the Taxol?,Nab-PTX,GPL 116,YLP 214 and LPL 616 groups were reduced by 16.3%,16.8%,10.1%,0.6%and 0.4%,respectively,at the same dose.Compared with Taxol?and Nab-PTX,GPL116 had the lowest reduction in pain threshold and delayed onset of pain.The oral system YLP 214 and LPL 616 showed no significant nerve pain.In terms of hematological toxicity,neutrophils decreased by 69.3%,59.5%and 22.3%in the high-dose administration of Taxol?,Nab-PTX and GPL 116 compared with the low-dose administration.The number of Gran#decreased by the least in the GPL 116 group,and the hematological toxicity was the least.However,the number of leukocytes and neutrophils decreased more significantly in the oral delivery system YLP 214 and LPL616 than in the injection system(Taxol?,Nab-PTX and GPL 116),and further improvement is needed.Conclusion:In this study,it was found that the paclitaxel delivery system for injection,GPL 116,had lower plasma exposure and a significant lung tissue distribution advantage compared with the marketed formulation Taxol?.Its neuropathic pain was significantly reduced compared to marketed formulations(Taxol?and Nab-PTX),and its neutropenia was improved,showing better safety.YLP 214 and LPL 616 have good gastrointestinal absorption characteristics and high oral bioavailability.Compared with Daehua Pharmaceutical’s DHP 107,YLP 214 has a significant distribution advantage in the lung and ovary,while LPL 616 has a prominent distribution advantage in the lung and stomach.At the same time,the two oral paclitaxel delivery systems are expected to enhance the anticancer effect of target tissues without causing obvious neuropathic pain.In summary,the three new paclitaxel delivery systems have obvious advantages in terms of pharmaceutical properties and safety compared with marketed preparations,and have good development potential. |
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