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Objective To establish an in vitro accelerated release method of triptorelin acetate microspheres with good in vi-tro/in vivo correlation(IVIVC). Methods The in vivo release of triptorelin acetate from microspheres was obtained by residual method in rats. Influences of pH value,concentration of ethanol,temperature,rotation speed and concentration of antiseptic on the in vitro accel-erated release were studied,then the correlation between in vitro accelerated release and in vivo release of the microspheres was estab-lished by adjusting the release conditions. Results The in vitro accelerated release medium of triptorelin acetate microspheres composed of 15%ethanol solution(containing 0.06%Tween 80 and 0.1%benzalkonium chloride)at 55℃with rotating rate of 200 r/min. The cumulative release of triptorelin acetate from microspheres was 87.35%at 30 h under accelerated release condition,equivalent to in vivo release for 30 days. The established in vitro accelerated release had a good correlation with that of in vivo(y=0.8845x+12.4510, R2=0.9938). Conclusion The in vitro accelerated release of triptorelin acetate microspheres could correlate well with in vivo release and has a potential application in rapid and effective evaluation of triptorelin acetate microspheres.
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Objective To establish an HPLC method to determine the related substances of metolazone and valsartan in com?pound metolazone tablets. Methods An Agilent Eclipse SB-C18 column (4.6 mm × 250 mm,5 μm) was used with 0.01 mol/L KH2PO4 buffer(pH=3.5)-acetonitrile as the mobile phase with gradient elution at a flow rate of 1.0 ml/min. The column temperature was 30℃ and the detection wavelength was 237 nm. Injection volume was 20 μl. Results Metolazone,valsartan and related sub?stance B of valsartan were separated completely. The calibration curves were linear within the range of 3-30μg/ml for metolazone, 0.1-2.0μg/ml for valsartan and 0.08-2.0μg/ml for related substane B of valsartan. The average recoveries were 102.97%,100.81%and 100.44%,respectively. The repeatability and intermediate precision met with requirements. The test solution was stable within 24 h. Conclusion The method is specific,sensitive,accurate and reliable,thereby can be used for the determination of metolazone and valsartan related substances in compound metolazone tablets.
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BACKGROUND/AIMS: This study investigated the protection provided by gabexate mesylate thermo-sensitive in-situ gel (GMTI) against grade III pancreatic trauma in rats. METHODS: A grade III pancreatic trauma model with main pancreatic duct dividing was established, and the pancreas anatomical diagram, ascites, and serum biochemical indices, including amylase, lipase, C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), were examined. The pancreas was sliced and stained with hematoxylin eosin and subjected to terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. RESULTS: Ascites, serum amylase, lipase, CRP, IL-6, and TNF-α levels were significantly increased in the pancreas trauma (PT) groups with prolonged trauma time and were significantly decreased after GMTI treatment. The morphological structure of the pancreas was loose, the acinus was significantly damaged, the nuclei were irregular and hyperchromatic, and there was inflammatory cell invasion in the PT group compared to the control. After GMTI treatment, the morphological structure of the pancreas was restored, and the damaged acinus and inflammatory cell invasion were decreased compared to the PT group. Moreover, the cell apoptosis index was significantly increased in the PT group and restored to the same levels as the control group after GMTI treatment. CONCLUSIONS: GMTI, a novel formulation and drug delivery method, exhibited specific effective protection against PT with acute pancreatitis therapy and has potential value as a minimally invasive adjuvant therapy for PT with acute pancreatitis.
Subject(s)
Animals , Rats , Amylases , Apoptosis , Ascites , C-Reactive Protein , DNA Nucleotidylexotransferase , Eosine Yellowish-(YS) , Gabexate , Hematoxylin , Interleukin-6 , Lipase , Methods , Necrosis , Pancreas , Pancreatic Ducts , PancreatitisABSTRACT
Objective To establish and validate a LC-MS/MS method for quantitative analysis of a new anti-stroke compound TID-101 in rat plasma and to study the pharmacokinetics and bioavailability of TID-101 self-(micro)emulsified drug delivery system (SMEDDS). Methods The plasma samples were treated with methanol for precipitating protein. The chromatographic separation was achieved with a acetonitrile-water mobile phase. Detection of TID-101 and the internal standard (IS) dexamethasone acetate was achieved by electrospray ionization(ESI)source in the negative ion mode at m/z 353.4→323.2 and m/z 433.4→353.4. The method was applied for pharmacokinetics study of TID-101 between SMEDDS in rats. Results The method was linear over TID-101 concen?tration range from 10-95 000 ng/ml with the correlation coefficients(r)of 0.9998. The intra-run and inter-run relative standard devia?tions(RSD)were less than 15%and the average absolute recovery values were 83.4-87.0%. The validated method was applied to a pharmacokinetic study in rats after intravenous administration of TID-101 fat emulsion injection and oral administration of TID-101 suspension and SMEDDS. The bioavailability of TID-101 API and SMEDDS was 2.8% and 14.9%,respectively. Conclusion The analysis method is simple,accurate,and sensitive for assaying the in vivo pharmacokinetic study of TID-101 in rats. SMEDDS could effectively enhance the oral bioavailability of TID-101.
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Objective To develop an LC-MS/MS method for the determination of ropivacaine in rat plasma. Methods The chromatographic separation was achieved on an Agela MP C18(2.1 mm×50 mm,3μm)analytical column. The multiple reaction monitor?ing(MRM)mode of the positive ion was adopted in the MS detection,and the precursors to the product ion transitions of m/z 275.2/126.1 and 326.0/291 were used to measure ropivacaine and internal standard(midazolam). Results The method was linear over the ropiva?caine concentration range of 0.5-250 ng/ml with the correlation coefficients r of 0.9946. The average inter-day precision values(RSD) were 1.32%-6.74%,the matrix effect values were 95.5%-102.6% and the average recovery values were 89.8%-104.7%. Conclu?sion The analysis methods for ropivacaine are simple,accurate and sensitive,thus can be used for the pharmacokinetic research of ropivacaine incorporated cubic liquid crystal in rat.
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Objective To investigate the anti-tumor activity of long-circulation thermosensitive liposom-loaded vincristine (VTSL)in vivo and in vitro. Methods The inhibitory effects of VTSL and vincristine injection(VCR)on sw620 cell and PANC cell were detected by MTT assay. The uptake capacity of HT-1080 was studied by using Cou-6-loaded liposome. Different xenograft nude mice models of HepG-2 and MCF-7 were established. To study anti-tumor effect of VTSL,drugs were given via tail and heat therapeu?tic area for 30 minutes,mice weight and tumor weight were recorded. To study anti-tumor effect of VTSL,drugs were given via tail vein and heat therapeutic areas for 30 min,mice body mass and tumor mass were recorded. Results After VTSL was given 72 h,the activ?ity of sw620 and PANC was less than 5%and 20%,respectively. VTSL showed stronger cytotoxic effect than vincristine. At the same dose,tumor inhibitory rate of VCR and VTSL on HepG-2 and MCF-7 bearing nude mice was 50%,69.7%,47.8%and 76.1%,respec?tively. There were significant differences in tumor weight after treatment. Conclusion VTSL enhances the cytotoxicity by heating. Loading vincristine into TSL increased cytotoxicity,and heating could promote the fusion of liposomes and cell membrane. Under the same dosage,VTSL showed much higher tumor inhibition rate than VCR,and there was a certain dose dependence. The results show that VTSL can be used in treatment of solid tumor and has the potential to expand vincristine clinical application.
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Objective To establish and validate the assay methods of release,content,content uniformity and related sub?stances of desvenlafaxine succinate (DVS) in extended-release tablets. Methods The ultraviolet spectrophotometric method was used to determine the DVS release from DVS extended-release tablets. The content uniformity,content and related substance were deter?mined by high-performance liquid chromatography(HPLC). To validate all the method,we respectively examined specificity,linearity, recovery rate,precision and stability,etc. Results The results showed that the analysis method for release was specific,the calibra?tion curve was linear in the range of 10-200μg/ml,and all the recovery,repeatability and intermediate precision met requirements. The method for detection of content and content uniformity was specific and linear in the range of 5-400μg/ml,the recovery,repeat?ability and intermediate precision met requirements. The method for related substances was specific and sensitive ,the linear and recovery rate met the requirements. All of the solutions were stable during 24 h at room temperature. Conclusion The analysis meth?od for release is simple,sensitive,specific and accurate,the method for content and content uniformity is accurate and reliable,and the method for related substances is specific,sensitive and accurate. These methods are suitable for quality control of DVS extended-release tablets.
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Objective To develop an LC-MS/MS method for simultaneous determination of metolazone and valsartan in beagle dog plasma.Methods The chromatographic separation was achieved on an Agilent Poroshell 120(2.1 mm ×30 mm × 2.7 μm)analytical column.The multiple reaction monitoring mode operating in positive ion was adopted in MS detection, and precursors to the product ion transitions of m/z 366.2/259, 436.2/291 and 423.4/207 were used to measure metola-zone, valsartan and internal standard ( losartan potassium) .Results The method was linear over the concentration range of 0.5 ng/ml-100 ng/ml for metolazone and 5-5000 ng/ml for valsartan, with the correlation coefficients ( r2 ) of 0.9937 and 0.9939, respectively.The average intra-day precision values ( RSD) were 2.09% -8.85% for metolazone and 2.36%-13.12%for valsartan.The matrix effect values were 87.73%-98.62%for metolazone and 99.03%-137.35%for valsartan.The average recovery was 75.74%-81.82%for metolazone and 83.89%-95.64%for valsartan.Conclu-sion This analytical method for metolazone and valsartan is simple, accurate and sensitive, so it can be used for pharma-cokinetic research of metolazone and valsartan immediate release tablets in beagle dogs.
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Under physiological conditions, many vital functions of the body are controlled by transient release of bioactive substances at a specific time and site. Based on the circadian rhythm character of disease and chronotherapeutic conceptions, pulsatile delivery system has been designed to achieve optimal therapeutic effect and reduce the toxic and side-effect. In recent years, more and more studies are focused on the pulsatile multiparticulate drug delivery system. Pulsatile multiparticulate system possesses many benefits, such as no risk of dose dumping, predictable gastric emptying, flexible release patterns and increased bioavailability. Based on these premises, the aim of this review is to summarize the major design methods of pulsatile multiparticulate and the research progress.
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Nowadays, nanotechnologies have shown wide application foreground in the biomedical field of medicine laboratory tests, drug delivery, gene therapy and bioremediation. However, in recent years, nanomaterials have been labeled poisonous, because of the disputes and misunderstandings of mainstream views on their safety. Besides, for the barriers of technical issues in preparation like: (1) low efficacy (poor PK & PD and low drug loading), (2) high cost (irreproducibility and difficulty in scale up), little of that research has been successfully translated into commercial products. Currently, along with the new theory of "physical damage is the origin of nanotoxicity", biodegradability and biocompatibility of nanomaterials are listed as the basic principle of safe application of nanomaterials. Combining scientific design based on molecular level with precision control of process engineering will provide a new strategy to overcome the core technical challenges. New turning point of translational medicine in nanotechnology may emerge.
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Objective To ch aracterize and evaluate in vitro and in vivo of the 10-hydroxycamptothecin (HCPT) loaded human serum albumin nanoparticle (HSA-NP) prepared by drug-liquid compound method. Methods The HCPT-HSA-NP was prepared with low weight polyethylene glycol drug-liquid compound and blank albumin nanoparticle. Then the in vitro evaluations were conducted with tests of entrapment efficiency, solution stability, accumulative release, morphous investigation and X-ray powder diffraction. At the same time, the primary pharmacodynamics comparison between HCPT injection and the nano preparation (8 mg/kg) was carried out on animal tumor model. Results The obtained HCPT-HSA-NP fitted to the basal features of nano preparation. The entrapment efficiency was averagely higher than 99% for each sample and the solution was stable. In vitro accumulative release study showed that the preparation had long-term release pattern over 100 hours. In vivo pharmacodynamics study showed that the HCPT-HSA-NP was significantly more effective than HCPT injection (P<0.01). Conclusion The drug-liquid compound method can be used to prepare HCPT-HSA-NP.
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Objective To establish a quick method to analyze vinorelbine ( NVB) in plasma of beagle dogs and study its pharmacokinetics of long-circulation and thermosensitive liposome loaded vinorelbine bitartrate.Methods The plasma was treated with liquid-liquid extraction after precipitation in methanol.The analysis was perfomed on a Venusil XBP C18 column(2.1 mm ×50 mm, 3 μm) at 35℃,the mobile phase consisted of methanol and water( containing 10 mmol/L ammonium acetate, 1%acetonitrile) 80∶20 and injection volume was 10μl.The type of mass spectrum was multireactive monitoring(MRM) in a positive mode.The monitor transitions were m/z 779.4-765.4 for vinorelbine and m/z 825.4-122 for vincristine.Results The concentration range from 10 to 2500 ng/ml had a good linearity ( r=0.0994).The precision, accuracy and extraction efficiency were acceptable.The plasma samples were stable for 10 days at -20℃ and 24 h at room temperature.Pharmacokinetic study in beagle dogs showed that the main parameters for injection and liposome were Cmax(833.51 ±150.42) and (1397.95 ±443.05)ng/ml, AUC(0-t) (577.16 ±223.57) and (1059.82 ±408.27) ng/ml· h, Cl(3014.64 ±1049.17)and 1633.10 ±551.77 ml/(h· kg), respectively.Conclusion A reliable HPLC-MS/MS method for vinorelbine analysis is established and can be applied to the pharmacokinetics study of liposome.The results show that liposome has a higher AUC, Cmax and longer Cl than injection.Meanwhile, liposome has a lower irritability.
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Despite tre mendous research efforts have been devoted to the analysis of nanoparticles (NPs)biohazard,the potential mechanism for nanotoxicity has not yet been syste mati-cal y elucidated.This review intends to point out the confusions about nanotoxicity in the field and tries to look into the mecha-nism from a new perspective.Currently,there are three puzzles:① no relationship between dose and toxicity could be observed in nanotoxicity;②there is a theory for the″size effects″,however, it cannot explain some cases contrary to the doctrine;③ NPs made of different materials with various sizes could have the same toxic effects through sti mulating oxidative stress.In fact, human body is co mposed of various biological molecules,and the biological function of a living syste m is reflected by the inter-actions and conversions of those molecules.NPs,on the other hand,are the invader of human body which has no ability to transport or convert or digest the foreigner.Thus,NPs could cause celldamage due to the physical blockage of micro-circula-tion,celldestruction due to membrane rando m insertion,and celldysfunction due to physical contacting with big biological mole-cules.The physical damages caused by various NPs could be divided into three categories:adhesion lesion,card inlay and puncture.Above al ,by analyzing wide spectrum of NPs varying in co mposition,shape and size,the author draws a conclusion that physical damage is the origin of nanotoxicity.
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Objective To establish an accelerated method that has good correlations with in vivo release data for formulation optimization and quality control purposes of thymopentin-loaded poly(DL-lactide-co-glycolide)(PLGA)microspheres. Methods In vivo thymopentin release from the microspheres was studied in Sprague-Dawley rats and relevant cumulative release curves were plotted. Key factors including release medium types,ethanol concentrations,surfactant concentrations and heating temperature were investigated for the in vitro accelerated release. The conditions for accelerated release were optimized to make the accelerated release cures fit the in vivo release well. The final optimized accelerated release method was validated in other two formulations. Results The final optimized accelerated release conditions were: 20% hydro-alcoholic solutions (V/V)and 0.06% Tween 80 (W/V)as the release media,gradient heating program (0-1 h at 40 °C,1-6 h at 45 °C and 6-30 h at 50 °C)as the media heating method. After fitted with the in vivo release curves,the correlation constant r2 of (8,13 and 28)×103 PLGA microspheres was 0.9783,0.9886 and 0.9780,respectively. Conclusion By introducing alcohol into the release media and applying gradient heating program,the reported accelerated method can be used in the formulation optimization and quality control of thymopentin-loaded PLGA microspheres.
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Drug delivery to lungs is becoming an important means of administration of some drugs for lung disease and some protein drugs with systemic effects. This article introduces the inhalation devices and particle characteristics,the two main features of dry powder inhalers (DPI), then reviews the advances on evaluation methods in vitro and in vivo for DPI, such as next generation pharmaceutical impactor (NGI), the imitation between particles and cells using electrodynamic levitation, hydraulic lung and dry powder endotracheal insufflator device, providing references for research and development of DPI evaluation methods.
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Pharmaceutical preparations can directly affect the administration methods and therapeutic effects of drugs , which is a priority for the research and development of the military specialized medicament .Foreign armies started pharma-ceutical formulation research very early , and some of their research concepts and strategies are worth learning from .In this paper , dosage forms were used as the classification factor and several formulations with distinct military characteristics were described in detail .The features of military specialized medicament were analyzed from the perspective of pharmaceutics , based on which future development in the formulation of military specialized medicament was predicted .
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Objective To investigate the pathologic mechanism of radiofrequency ablation ( RFA ) combined with intravenous infusion of thermosensitive liposome encapsulated vinorelbine (TL-Vin) in treating liver tumors, and to analyze the effect of combination therapy on the long-term survival rate. Methods H22 liver adenocarcinoma tissue was subcutaneously implanted into ICR mice to establish the animal models. At the first experimental period, 40 mice were randomly and equally divided into 5 groups to receive different therapeutic scheme (using different TL-Vin concentrations). Twenty-four hours after the treatment the tumor specimens were collected, the necrotic areas were measured separately, and the optimal TL-Vin concentration was determined. At the second experimental period, 13 mice were randomly selected to receive treatment. Half an hour after the treatment the tumor tissues were collected and the TL-Vin concentration within the tumor was determined. At the third experimental period, 32 mice were randomly and equally divided into 4 groups, and 90 days after treatment the tumor growth curve was drawn. The survival rate was compared between each other of the groups. Results Compared with pure RFA group, TL-Vin + RFA significantly increased tumor coagulation extent (P0.05). Tumor coagulation area in TL-Vin + RFA group was bigger than that in free-VIN + RFA group at the concentration of 10 mg/kg [(341.8 ± 65.4)mm2 vs (225.3 ± 25.4)mm2, P < 0.01]. In TL-Vin group the coagulation margin was clear. The mean intratumoral Vinorelbine accumulation in TL-Vin + RFA group was 10 folds of that in free-Vin group [(1 156.5 ± 158.3)ng/ml vs (194.5 ± 52.3)ng/ml, P = 0.005]. TL-Vin +RFA had better survival result than that of RFA alone (37.6 ± 20.1 days vs. 23.4 ± 5.0 days, P=0.015), as well as than that of free-Vin + RFA [(37.6 ± 20.1)days vs (23.3 ± 1.2)days, P = 0.016]. Conclusion Thermosensitive liposomal chemotherapies (Vinorelbine) can be selectively delivered at the edge of RFA coagulation area and thus effectively increase RFA-induced tumor coagulation and prolong the end-point survival in experimental mice.
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Objective To prepare thermosensitive in situ hydrogels (ISG) of gabexate mesilate and establish quality control method.Methods ISGs were prepared using PF127 and PF68 as matrix, evaluated by gelling temperature , gelling time, gelling ca-pacity in vitro, and determinated by HPLC.Results The gelling time of ISG was (1.8 ±0.2)min, with gelling temperature at 31℃. When the gel temperature rose to 31℃, the viscosity of ISG increased dramatically .The linear range of HPLC determination curve was 10-350 μg/ml, with an average recovery of 99.63%( RSD=0.88%) .Conclusion Preparation of the gel with controllable quality is simple and easy .The determination method is reliable for gabexate mesilate thermosensitive in situ hydrogels .
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An on-line solid phase extraction ( SPE ) coupled with HPLC-MS/MS method was developed to determine S-ammuxetine and R-ammuxetine in rat plasma. The sample preparation consisted of the following steps:A protein precipitation extraction used methanol and acetonitrile ( 50:50 , V/V ); an on-line SPE treatment to remove most matrixes in plasma;an enrichment and separation step used a C18 analytical column. S-and R-ammuxetine were determined by tandem mass spectrometry. The SPE column was a Retain PEP Javelin (10 mm × 2. 1 mm × 5 μm), while the chromatographic separation was achieved using a ZORBAX SB-C18 (50 mm × 2. 1 mm × 3. 5 μm) analytical column with an isocratic mobile phase composed of acetonitrile-water-formic acid (40:60:0. 1, V/V/V, 0. 3 mL/min). The selected reaction monitoring mode of the positive ion was performed and the precursor to the product ion transitions of m/z 292 . 1/154 . 0 and m/z 260. 4/116. 2 were used to measure S-ammuxetine, R-ammuxetine and internal standard (propranolol). The method was linear over a concentration range from 0 . 2 to 1000 μg/L with the correlation coefficients of 0 . 9903 and 0 . 9951 . The average intra-day precision values were 1 . 2% -12 . 0% for S-ammuxetine and 0. 4%-11. 2% for R-ammuxetine, respectively. The average recoveries were 94. 2%-101. 6% for S-ammuxetine and 94. 3% -109. 4% for R-ammuxetine. Compared to the literature, the sensitivity of this method increased dramatically. The present method has been successfully applied to the preclinical rat research of ammuxetine isomers following intragastric administration.
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Liposomes can be cleared by the reticuloendothelial system (RES) when it is in the blood circulation in the body. And they can accumulate in the organs rich in RES in the body by passive targeting. Targeting of the liposomes is an important factor for its use as a drug carrier, and particle size as well as surface charge are important for its in vivo targeting. In this paper, studies on the influences of particle size and surface charge of the liposomes on cell binding and phagocytosis mechanism were reviewed. A comprehensive review on passive targeting effect of the particle size and surface charge of liposomes on blood, liver, spleen as well as tumor tissue was made. At last, an outlook for future research directions was made.