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@#An HPLC pre-column derivatization detection method was established to detect and analyze the formaldehyde and acetaldehyde in polysorbate 80 and polysorbate 20 from different manufacturers.The effects of aldehyde and acetaldehyde on the aggregation of adalimumab under different conditions were monitored.Based on the control of genotoxic impurities and the influence on the stability of monoclonal antibody preparations, the control limits of the two chemicals were preliminarily obtained.2, 4-dinitrophenylhydrazine (2, 4-DNPH) was applied as the derivatization reagent in HPLC pre-column derivatization; acetonitrile and water were used as mobile phase to perform a gradient elution on a C8 (4.6 mm × 150 mm, 5 μm) chromatographic column.The detection wavelength was 360 nm, and the external standard method was used for quantification.Verification results showed that the method was suitable for the quantitative analysis of trace formaldehyde and acetaldehyde in polysorbate 80 and polysorbate 20 . The detection and analysis of formaldehyde or acetaldehyde in different batches of polysorbate 80 and polysorbate 20 from different manufacturers showed that the content of formaldehyde and acetaldehyde were quite different. The content of formaldehyde and acetaldehyde in polysorbate 80 were significantly higher than those of polysorbate 20. After monitoring the changes of adalimumab aggregates treated by formaldehyde and acetaldehyde by size exclusion chromatography (SEC), it was found that the effect of formaldehyde on adalimumab aggregation was significantly higher than that of acetaldehyde.According to the requirements of ICH M7 (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk), the impurity limits of formaldehyde and acetaldehyde in polysorbate 80 and polysorbate 20 for monoclonal antibody preparations were calculated from the perspective of risk assessment.Combined with the influence on the aggregation stability of monoclonal antibodies, the preliminary limis for acetaldehyde and acetaldehyde were recommended to be ≤ 7 μg/g and ≤ 765 μg/g, respectively.
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@#Pharmaceutical excipients of animal origin, an important part in pharmaceutical excipients, are widely used in pharmaceutical preparations.However, compared with the pharmaceutical excipients of other origins, pharmaceutical excipients of animal origin have more special requirements in many aspects, such as raw materials, production, quality control, storage, supervision, etc.Chinese Pharmacopoeia 2020 first included the Guideline for Pharmaceutical Excipients of Animal Origin, which introduces the basic ideas and technical requirements for the life cycle quality control of pharmaceutical excipients of animal origin based on the risk management concept.This article illustrates the specificity of the pharmaceutical excipients of animal origin, and interprets the main contents of this guideline in conjunction with relevant domestic and foreign regulations and technical documents, thereby providing comprehensive reference for the implementation of the guideline.
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@#For the quality control of cetomacrogol 1000, a gas chromatographic method for the determination of residual impurities in cetomacrogol 1000, such as ethylene oxide, 1, 4-dioxane, ethylene glycol, diethylene glycol and triethylene glycol, was established and validated.The DB-1 column with headspace injection was used to detect ethylene oxide and 1, 4-dioxane with the inlet temperature of 150 °C, the FID temperature of 250 °C, the headspace equilibration temperature of 70 °C and the equilibration time of 45 min.The VF-17MS column with liquid injection was used to detect ethylene glycol, diethylene glycol and triethylene glycol with the inlet temperature of 270 °C, and the FID temperature of 290 °C.The results showed that ethylene oxide and 1,4-dioxane have a good linearity within their specified addition amount ranges (r > 0.999), with the RSD of precision of below 8.0% and the average recovery rates of 90.6% and 101.2%; and that ethylene glycol, diethylene glycol and triethylene glycol also have a good linearity between 3 ? 60 μg/mL (r > 0.999), with the RSD of precision of below 3.0%, and the recovery rates of 96% ~ 103%.The method established in this study has good specificity, linearity, precision and recovery rate, which can effectively detect the multi-component and trace impurities.
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@#As one of the most important biological drugs, protein and peptide drugs have been increasingly used in the prevention, diagnosis and treatment of diseases in recent years. However, most of them need to be injected and lack of long-acting formulations, which brings many troubles to patients suffering from chronic diseases. In this review, we summarized the strategies for engineering long-acting formulations for proteins and peptides via preparation means, including extended-release injection, implant, oral preparations and transdermal drug delivery systems, and analyzed their release mechanisms, research advances, advantages and shortcomings, thereby providing potential approaches for promoting the formulation improvement of these drugs.
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@#To improve the current quality standards of polysorbate 80 and provide reference recommendations for the revision of the quality standards of polysorbate 80 in the fourth part of China Pharmacopoeia(2015 Edition). A total of 16 batches of polysorbate 80 samples from 6 domestic and foreign production companies were studied, optimize the detection method for some impurities. Adjust the split ratio of the ethylene oxide and dioxane check items, and appropriately increase the concentration of the reference solution solution and change the solvent. In the ethylene glycol and diethylene glycol items, the concentration of the reference solution and the internal standard solution were appropriately increased. The infrared identification and the triethylene glycol check items were added to the quality standards, and we carry out corresponding methodological investigation on the improved method. The results showed that the improved methods had good specificity, precision, linearity and recovery rate. The improved quality standard is more suitable for the detection of polysorbate 80, and can increase the quality standards of polysorbate 80 from safety and standardization.
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@#Taking plastic packaging materials as an example, this paper mainly summarizes the general principles of pharmacopoeias and guiding principles of relevant government departments related to the compatibility studies of drugs and packaging materials at home and abroad, with much reference to relevant monographs and literature. The purpose and specific methods of extraction and interaction studies are summarized and discussed. The existing problems and solutions in compatibility research are also proposed in this review to provide some refe-rence for researchers in relevant fields.
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@#The gas chromatography method was developed for the determination of ethylene glycol, diethylene glycol and triethylene glycol in poloxamer 188 to provide scientific basis for the quality control. The samples was separated on column VF-17ms(30 m×0. 53 mm, 1. 0 μm)with temperature programming, inlet temperature was 270 °C, detector temperature was 290 °C and the split ratio was 10 ∶1. The method showed great linearity over the range of 6-15 μg/mL(r≥0. 999). The injection precision(n=8)of the three residual impurities were 3. 3%, 3. 0%, 2. 3% and the average recoveries were 99. 05%(RSD=2. 9%, n=9), 102. 20%(RSD=4. 0%, n=9), 101. 91%(RSD=3. 1%, n=9), respectively. The analytical method is specific, accurate and sensitive, which is suitable for the determination of ethylene glycol, diethylene glycol and triethylene glycol in poloxamer 188, providing reference and guidance for the production and quality control of poloxamer 188.
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@#To conduct the characterization of its pharmacokinetics in rats of nifedipine sustained-release pellets and to study the relationship between the pellets and CYP3A4 activity. A gradient HPLC method was developed to simultaneously determine 6β-hydroxycortisol and hydrocortisone. CYP3A4 activity of rats was quantified by urinary ratio of 6β-hydroxycortisol/hydrocortisone after intravenous injection of hydrocortisone as a biomarker. HPLC method was also developed to quantify the drug concentration in plasma of rats, and the studies of pharmacokinetics were performed after oral administration of single dose of two formulations: Nifedipine matrix sustained-release pellets and nifedipine tablet(using as control). The results showed that the ratio of ten rats was 0. 271±0. 129. cmax of nifedipine sustained-release pellets decreases by nearly 70%, tmax significantly increased by 400% and t1/2 and MRT significantly increased by 230% compared to control. Nifedipine sustained-release pellets had a significant sustained-release property compared to the control and CYP3A4 activity affected its pharmacokinetics behavior.
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@#The aims of this research were to constitute and evaluate one targeting anticancer co-delivery system for both micro-molecularchemotherapeutic drugs(docetaxel, DTX)and small interfering RNA(siRNA)expressed by COX-2. The nanoparticles composed of poly(D, L-lactide-co-glycolide)(PLGA)bearing disulfide-linkaged reducible polyethyleneimine(PEIss)covered by hyaluronic acid(HA). Meanwhile, HA-PEI-PLGA nanoparticles were prepared as control. Firstly, the solvent evaporation was used to the particles which exhibited a core-shell structure with a uniform size of 150-200 nm. The cumulative drug release in two kinds of PBS media(pH 7. 4 and pH 5. 0)during 72 hours indicated that DTX-loaded nanoparticles had sustained-release effect within 24 hours. The cumulative release of DTX of HRPSP NPs in PBS pH 5. 0 was 10%-25% more than that in PBS pH 7. 4, which demonstrated that favored release of DTX from nanoparticles could be achieved in acidic tumor microenvironment. Then, the highest transfection efficiency was observed after 14-16 h incubation at N/P ratio of 40/1. Following the saturation of CD44 receptor, the mean fluorescence intensity of HRPSP NPs from the cells decreased drastically in the case of saturation with free HA before. However, there existed no significance in the fluorescence of RPSP NPs between the cells with and without saturation with free HA, which indicated the nanoparticles′ targeting potential toward tumor cells. In the Western blot, the relative silencing efficiency of Bcl-2, bax, capase-3 and COX-2 mRNAprotein was calculated. In comparison to the control group, the silence efficiencies of bax and capase-3 were both significantly increased while that of Bcl-2 was evidently reduced, particularly in siCOX-2/HRPSP NPs group(P< 0. 01). The similar results were obtained in the silence efficiency of COX-2 protein in which the COX-2 quantity on mRNA and protein decreased. The results suggest that the nanoparticles could achieve the synergistic effect on the combinatorial delivery of siRNA and lipophilic anti-tumor drugs.
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@#Graft copolymerization is one of the most effective methods to improve the performance of pullulan and extend its applications. This paper attempts to review the recent progresses in the preparation and application of graft copolymers of pullulan as pharmaceutical carriers from different synthesized polymers and the properties of graft copolymers of pullulan. The problems of pullulan based graft copolymers in drug release system are expounded, and the future development in this field direction is presented.
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This study is to prepare the in situ forming sustained-release injection which can perform sustained release behavior at the periodontal site for 7 days and to evaluate its in vitro and in vivo properties. After preparation of in situ forming sustained-release injection the in situ time was studied. And the surface of the solid injection was characterized by SEM. The rheological curve at 0 degrees C, 25 degrees C, 37 degrees C was determined and the impact of the temperature on the viscosity was examined. The in vitro release behavior was investigated. At last, rabbit periodontitis model was established to study its pharmacokinetics. The injection was stable, hard to stratify and decompose. The in situ forming time was about 6 seconds. It can easily adhere into periodontal pockets. There were lots of holes on the surface of the solid injection for the drug to diffuse. The drug releasing curves could be fit by Korsmeyer-Peppas equation. The drug smoothly released for 7 days at pH 7.4 PBS buffer with a very slight burst release and maintained a certain concentration. In vivo pharmacokinetics results indicated that after administration with the in situ forming injection, achievement of tinidazole (TNZ) concentration in gingival crevicular fluid (GCF) was more comparable and long-lasting than usual solution of TNZ management and relatively constant TNZ levels were attained until 168 h. All these results supported the prospect of tinidazole in situ forming sustained-release injection in clinical applications.
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In this study, indomethacin (IND) loaded solidified-polymeric micelles (IND-SPM) were prepared. Their in vitro characteristics were investigated. Methoxy-poly(ethylene glycol) poly(D, L-lactide) copolymer (mPEG-PDLLA) was used as IND carrier. The preparation of IND-SPM was conducted by solution-absorption method and evaporation by rotary evaporator. Polyplasdone XL-10 was used as adsorbent. The solution-absorption method was conducted by the following procedure; IND and mPEG-PDLLA were dissolved in acetone, followed by addition of polyplasdone XL-10 and stirred to obtain a suspension. The powder of IND-SPM was simply obtained after the organic solvent was completely evaporated. More than 90% (w/w) of IND (20 mg) in the powder was dissolved in 250 mL PBS within 30 min. DSC, 1H NMR and SEM results proved that IND was encapsulated within mPEG-PDLLA. The solubility of IND in the system increased 4.6 times with the highest amount of copolymer. The solidified particles were found to be suitable for the formulation of tablets or capsules.
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Aim: To prepare ropivacaine hydrochloride multivesicular liposomes, and to study the physicochemical properties and drug release behavior in vitro. Methods: Ropivacaine hydrochloride multivesicular liposomes were prepared by the multiple emulsion method. Single factor experiments were utilized to study the factors which affect the encapsulation efficiency of multivesicular liposomes. The formulation and pharmaceutical process were optimized by Box-Behnken experimental design, with the factors of encapsulation efficiency as the criteria. Three batches of the optimized multivesicular liposomes were prepared, and the encapsulation efficiency and in vitro release behavior were studied. Results: The particle size of the optimized multivesicular liposomes was uniform and 85% of them were well distributed in the range of 7-30 μm. The encapsulation efficiency was up to 90% when the ratios of lipid to drug, phospholipids to cholesterol and the amount of triolein was 1. 328:1(w/w) ,1.5: 1(w/ w) and 6 mmol/L, respectively. The release profile in vitro fitted to a first-order kinetics with the period of release up to 48 h in PBS buffer under 37 ℃. Conclusion: Ropivacaine hydrochloride multivesicular liposomes showed high encapsulation efficiency and significant sustained-release feature.