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Objective To optimize the formulation and preparation of diphenhydramine hydrochloride and caffeine orally disintegrating tablet. Methods Melt granulation technology of steric acid and API was used to mask the unpleasant tasting of diphenhydramine hydrochloride. The tablets were prepared by direct pressing the dry powder with CCMC-Na as disintegrating agent. The formulation was optimized by orthogonal experiments to achieve the shortest disintegration time and the best taste correction. Results The optimized formula of orally disintegrating tablet was as follows： diphenhydramine hydrochloride 25 mg, caffeine 60 mg, stearic acid 25 mg, aspatan 40 mg, blueberry essence 7 mg, mannitol 45 mg, MCC 210 mg, CCMC-NA 25 mg, SDS 8 mg and magnesium stearate 5 mg. Conclusion This preparation method for orally disintegrating tablet of diphenhydramine hydrochloride and caffeine is practical and easy for quality control.
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Objective: To optimize the formula of bromhexine hydrochloride dry powder inhalations (BH DPIs). Methods: BH DPIs were prepared by freezing-drying combined with an air-jet milling method. Three factors, including the weights of mannitol (X1), leucine (X2) and poloxamer 188 (X3) in the formula were known to be associated with the quality of BH DPIs. A central composite design was used to investigate the effects of the three factors on the response angle (Y1), fine particle fraction (FPF, Y3) and aerody-namic diameter (Y4). Response surface and overlay contour plot were delineated according to the best-fit mathematic models. Opti-mum formula was selected by overlay contour plot. Results: The quantitative relationships between the three factors and the three re-sponses were obtained. The optimal formula was mannitol﹕leucine﹕poloxamer 188 (2. 4: 2. 22: 0. 05) in the excipients. The pre-dicted and observed values of the optimum formula were similar. Conclusion: The multi-objective simultaneous optimization of the for-mula of BH DPIs is achieved by central composite design-response surface methodology.
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Objective:To prepare aripiprazole oral disintegrating tablets , investigate the formula and evaluate the quality .Meth-ods:The formula of aripiprazole oral disintegrating tablets was investigated by a factorial experiment design .The aripiprazole particle size distribution ( X1 , D90/μm) , the ratio of mannitol to microcrystalline cellulose ( X2 ,％) and the amount of disintegration ( X3 ,％) were selected as the independent variables , and the tablet hardness ( Y1 , N) , the disintegration time ( Y2 , s) and the dissolution in 30 min ( Y3 ,％) were used as the dependent variables to ultimately determine the optimal formula .The dissolution profile of aripiprazole oral disintegrating tablets and the reference preparation in four dissolution media were compared by f2 similarity factor, and the stability of aripiprazole oral disintegrating tablets was investigated by accelerated stability testing .Results: The results of factorial experiment design of variance analysis showed that the filler ratio had significant effect on the tablet hardness (P<0.05), the amount of disinte-grant and the filler ratio had significant effect on the disintegration time (P<0.05), and the aripiprazole particle size had significant effect on the drug dissolution ( P<0.05 ) .The optimal formula of aripiprazole oral disintegrating tablets was as follows: the particle size D90 of aripiprazole was 20-40μm, the amount ratio of mannitol to microcrystalline cellulose was 2.5:1, and the amount of disinte-gration was 5.0％.Aripiprazole oral disintegrating tablets prepared with the optimal formula had higher hardness , shorter disintegration time and faster drug dissolution , and the dissolution profiles were similar with those of the reference preparation .The relevant sub-stances showed no significant increase during the accelerated stability testing , and the quality was satisfactory .Conclusion:The formu-la of aripiprazole oral disintegrating tablets is reasonable , the preparation process is feasible and the quality is controllable .
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Objective:To explore the effects and mechanism of liraglutide on nitrogen monoxide (NO) release in human umbilical vein endothelial cells in the state of hypoxia and high glucose.Methods:A model of hypoxia and high glucose was established by using isolation and culture of primary human umbilical vein endothelial cells (HUVECs) in vitro.HUVECs were incubated with liraglutide and/or exendin (9-39) for 4 h.The metabolic ability of cells was detected by MTT assay,the activity of lactate dehydrogenase (LDH) was measured by a colorimetric method,and the levels of extracellular NO were measured by a nitrate reductive enzymatic method.The endothelial nitric oxide synthase (eNOS) mRNA expression was detected by reverse transcription-polymerase chain reaction (RT-PCR).Results:Compared with the model group,liraglutide could significantly increase cell metabolic ability,reduce LDH release,increase NO release and eNOS mRNA expression (P<0.05 or P<0.01).The above effects of liraglutide were partly inhibited by glucagon like peptide-1 (GLP-1) receptor antagonist exendin (9-39)(P<0.05).Conclusion:Liraglutide can improve endothelial relaxation function in HUVECs in the state of hypoxia and high glucose in vitro.The effect might be related to up-regulating eNOS mRNA expression and promoting NO release.
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Objective:To prepare and optimize the formula of metoclopramide orally disintegrating tablets, and investigate the in vitro drug dissolution behavior. Methods:The formula was optimized by full-factorial experiment design, the ratio of mannotil to micro-crystalline cellulose ( X1 ) and the amount of disintegrating agent ( X2 ,%) were selected as the independent variables, and the friabili-ty ( Y1 ,%) , disintegration time ( Y2 , s) and metoclopramide dissolution ( Y3 ,%) were used as the dependent variables. The release rate of metoclopramide orally disintegrating tablets in different dissolution media was studied. Results:The optimum formula of meto-clopramide orally disintegrating tablets was as follows:the ratio of mannotil to microcrystalline cellulose was 2. 5∶ 1, and the amount of disintegrating agent was 6. 5%. The dissolution of metoclopramide orally disintegrating tablets in the different dissolution media was o-ver 80%. Conclusion:The formula design is reasonable, the preparation process is feasible and the quality can be controlled.
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Objective:To establish a method to determine the content of lidocaine hydrochloride in buccal adhesive tablets contai-ning carbomer as an excipient by HPLC. Methods:Calcium chloride was used to precipitate carbomer in buccal adhesive tablets. The HPLC analysis was performed on a Welch C18 column(250 mm × 4. 6 mm,5 μm)with the column temperature of 40℃. The mobile phase was the mixture of 0. 05% sodium acetate solution(added 50 ml acetic acid into 930 ml distilled water,adjusting pH to 3. 40 with 1 ml·min-1 sodium hydroxide solution)and acetonitrile(70:30). The flow rate was 1. 0 ml·min-1 ,the detection wavelength was at 254 nm and the injection volume was 20 μl. Results:Within the range of 0. 10-2. 00 mg·ml-1 ,there was a good linear rela-tionship between the concentration and the peak area of lidocaine hydrochloride(r=0. 999 9). The average recovery was 100. 2%( RSD=1. 4%,n=9). Conclusion:The established method is simple,accurate and reproducible,which can be applied to determine the content of lidocaine hydrochloride in buccal adhesive tablets.
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Objective:To prepare and optimize candesartan cilexetil tablets,and study the stability preliminarily. Methods:The formula was optimized by Box-Behnken experiment design,the ratio of lactose to pregelatinized starch( X1 ),the amount of disintegrant ( X2 ,%)and the amount of lubricant( X3 ,%)were selected as the independent variables,and weight difference( Y1 ,%),friability ( Y2 ,%),disintegration time( Y3 ,%)and candesartan cilexetil dissolution( Y4 ,%)were the dependent variables. The release rate of candesartan cilexetil tablets and the reference tablets were compared by similarity factor( f2 value). Preliminary stability was studied by high-temperature test,high-humidity test and illumination test. Results:The optimal formula of the tablets was as follows:the ratio of lactose to pregelatinized starch was 7:1,the amount of disintegrant was 5. 5%,and the amount of lubricant was 0. 5%. The f2 for the candesartan cilexetil tablets and the reference tablets in different dissolution meda was 60. 62,73. 34,66. 95 and 68. 60,respec-tively. Conclusion:The formula design is reasonable,the preparation process is feasible and the quality can be controlled.
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Objective:To prepare resveratrol microemulsions by high pressure homogenization method and characterize the microe-mulsions. Methods:Using the particle size, polydispersion index and encapsulation efficiency as the indicators, the independent varia-bles of the preparation were inspected, and the microemulsions were characterized. The stability of resveratrol microemulsions was stud-ied by long term stability test preliminarily. Results:The mean particle size, polydispersion index and zeta potential of resveratrol mi-croemulsions was (231 ± 37. 8) nm, 0. 228 ± 0. 047 and ( -42. 5 ± 4. 3) mV, respectively. The microemulsions were found to be small and spherical with smooth surface under a transmission electron microscope. Long term stability studies showed that the microe-mulsions were stable in 3 months after stored at 25℃. Conclusion:The preparation process of high pressure homogenization method for resveratrol microemulsions is simple and feasible.
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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 prepare vinorelbine bitartrate long-circulation liposomes by pH gradient loading methods and make characterization. Methods The impact of hydration temperature and extrusion times on the blank liposome particle size was investigated;and the incubation temperature and in duration on size and encapsulation percentage of drug loading liposome particle was tested. The vinorelbine bitartrate long-circulation liposome was characterized for particle size,polydispersion index, Zeta potential,morphology,and was studied for long term stability. Results The particle size,Zeta potential,polydispersion in-dex of long-circulation liposomes were (96. 4±27. 2) nm,(0. 162±0. 042),(-26. 7±3. 5) mV,respectively. The liposomes were small,unilamellar and spherical with smooth surface under transmission electron microscopy. Long term stability studies showed that the liposomes were stable for up to 3 months after storage at 5 ℃ . Conclusion The preparation technology for the vinorel-bine bitartrate long-circulation liposome by pH gradient loading methods is feasible.
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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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Objective:To establish an HPLC method for the simultaneous determination of eprosartan/hydrochlorothiazide tablets. Methods:Isocratic separation was achieved on a Phenomenex C18 column(250 mm × 4. 6 mm, 5 μm) using the mobile phase com-posed of 0. 5% formic acid-acetonitrile(60∶40, pH 2. 80). The flow rate was 1. 0 ml·min-1, the detection wavelength was 272nm, the column temperature was 30℃ and the injection volume was 20μl. Results:The linearity between peak area and concentration was observed within the range of 60. 0-1 200. 0 mg·L-1(r=0. 999 9) for eprosartan and 1. 25-25. 00 mg·L-1(r=0. 999 9) for hydro-chlorothiazide. The mean recovery of eprosartan and hydrochlorothiazide was 100. 02%(RSD=0. 35%, n=9) and 97. 93%(RSD=1. 54%, n=9), respectively. Conclusion:The method is simple, sensitive and accurate, and can be applied in the determination of eprosartan/hydrochlorothiazide tablets.
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Objective:To optimize the formula of mirtazapine orally disintegrating tablets by orthogonal experiment and determine the stability preliminarily. Methods:The formula was optimized by orthogonal experiment based on 4 impacting factors:the amount of mannotil (A), microcrystalline mellulose (B), low substituted hydroxypropyl cellulose (C) and cross-linked polyvinylpyrrolidone ( D) , respectively with 2 indices of disintegration time and dissolution. The release rate of the orally disintegrating tablets and the ref-erence tablets was studied by similarity factors. The stability was respectively studied by high temperature test, high humidity test and photostability test. Results:The optimum formula of the tablets was as follows:the amount of A, B, C and D was 70, 20, 2. 5 and 10 mg, respectively. The f2 for the orally disintegrating tablets and the reference tablets in the dissolution medium was 63. 38. Conclu-sion:The formula is reasonable, the preparation process is feasible and the quality is stable.
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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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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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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.