Pharmacokinetics of nifedipine sustained-release tablets in healthy Chinese volunteers

Aim To establish a LC-MS method for determining the concentration of nifedipine in human plasma and to evaluate the pharmacokinetic characteristics of nifedipine sustained-release tablets. Methods A XB-C18 （5 μm, 4.6 mm ×150 mm） column and a mobile phase of methanol： 0.01 mol·L^-1ammonium acetate （60：40, V/V） were used to separate nifedipine, the detections was accuracy under atmosperic pressure electronic spray ionization （AP-ESI） mode and ion mass spectrum （m/z） of 314.9 [M＋H]^＋ for nifedipine, and 320.8 [M＋H]^＋ for lorazepam （Internal Standard, IS）. Results The linear range of nifedipine was 0.3 - 80 ng·mL^-1 （ r = 0.9997）, and the limit of quantitation （LOQ） was 0.3 ng·mL^-1. The nifedipine pharmacokinetic parameters after a single dose of 20 mg nifedipine sustained-release tablets test （T） or reference （R） were as the followings, t1/2 （6.73 ± 2.00） h and （7.04 ± 2.18） h, Tmax （4.28 ± 0.70） h and （4.48 ± 0.70） h, Cmax（39.66 ± 10.58） ng·mL^-1 and （40.19 ± 10.97） ng·mL^-1, AUC0-36 （391.63 ± 108.55） ng·mL^-1·h and （387.57 ± 121.51） ng·mL^-1·h, and AUC0-∞ （408.28 ± 121.16） ng·mL^-1·h and （406.15 ± 133.13） ng·mL^-1·h. The relative bioavailability of nifedipine sustained-release tablets （test） was （103.02 ± 13.93） %. Conclusion LC-MS method for the determination of concentrations of nifedipine in human plasma was sensitive and accurate, and could be used in nifedipine bioavailability and pharmacokinetic studies.

Nerve growth factor-basic fibroblast growth factor poly-lactide co-glycolid sustained-release microspheres and the small gap sleeve bridging technique to repair peripheral nerve injury

We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique.Multiple growth factors play a synergistic role in promoting the repair of peripheral nerve injury;as a result,in this study,we added basic fibroblast growth factors to the microspheres to further promote nerve regeneration.First,in an in vitro biomimetic microenvironment,we developed and used a drug screening biomimetic microfluidic chip to screen the optimal combination of nerve growth factor/basic fibroblast growth factor to promote the regeneration of Schwann cells.We found that 22.56 ng/mL nerve growth factor combined with 4.29 ng/mL basic fibroblast growth factor exhibited optimal effects on the proliferation of primary rat Schwann cells.The successfully prepared nerve growth factor-basic fibroblast growth factor-poly-lactide-co-glycolid sustained-release microspheres were used to treat rat sciatic nerve transection injury using the small gap sleeve bridge technique.Compared with epithelium sutures and small gap sleeve bridging alone,the small gap sleeve bridging technique combined with drug-free sustained-release microspheres has a stronger effect on rat sciatic nerve transfection injury repair at the structural and functional level.

Combustion Characteristics of Solid Sustained-Release Energetic Materials

A solid sustained-release energetic material sample,an eruption device and a complete test system were prepared further to analyse the combustion characteristics of solid sustainedrelease energetic materials.The high-temperature heat flux generated by the combustion of the samples from the eruption device was used to penetrate the Q235 target plate.In addition,the meaning and calculation formula of energy density characterising the all-around performance of heat flux were proposed.The numerical simulation of the combustion effect of samples was carried out.According to the data comparison,the numerical simulation results agreed with the experimental results,and the maximum deviation between the two was less than 8.9%.In addition,the structure of the combustion wave and high-temperature jet was proposed and analysed.Based on theoretical analysis,experimental research and numerical simulation,the theoretical burning rate formula of the sample was established.The maximum error between the theoretically calculated mass burning rate and the experimental results was less than 9.8%.Therefore,using the gas-phase steady-state combustion model to study the combustion characteristics of solid sustained-release energetic materials was reasonable.The theoretical burning rate formula also had high accuracy.Therefore,the model could provide scientific and academic guidance for the theoretical research,system design and practical application of solid sustained-release energetic materials in related fields.

Nifedipine对烟草花粉萌发、花粉管生长及生殖核分裂的影响

用细胞学和统计学方法研究了Ｃａ２＋ 通道专一性阻滞剂ｎｉｆｅｄｉｐｉｎｅ（Ｎｉｆ）对烟草（Ｎｉｃｏｔｉａｎａ ｔａｂａｃｕｍＬ．）离体花粉萌发、花粉管生长及生殖核分裂的影响。１０－ ４ ｍ ｏｌ／ＬＮｉｆ可抑制花粉萌发。Ｎｉｆ对花粉管生长的影响与其浓度和处理持续时间有关，１０－ ４ ｍ ｏｌ／Ｌ Ｎｉｆ始终抑制花粉管生长；而１０－ ７～１０－ ５ ｍ ｏｌ／ＬＮｉｆ在较短时间内起不同程度的促进作用，之后逐渐过渡为抑制花粉管生长。较高浓度处理可使花粉管形态趋向异常，细胞质流动趋于停滞。Ｎｉｆ抑制生殖核的有丝分裂，相对推迟分裂高峰。Ｎｉｆ使花粉管中的金霉素（ＣＴＣ）荧光趋于减弱，表明Ｎｉｆ通过抑制Ｃａ２＋ 通道活性产生生理效应。

Nifedipine对缺血突触体游离钙和氨基酸释放的影响

目的：通过Nifedipine对缺血突触体内游离钙浓度及氨基酸释放量的影响，初步探讨其脑缺血保护作用与兴奋性氨基酸（EAA）和抑制性氨基酸（IAA）释放关系。方法：营养液中去除糖和氧建立大鼠脑突触体缺血模型，检测静息及高钾去极化状态下缺血突触体游离钙浓度及EAA和IAA释放量的变化，并检测Nifedipine对此变化的影响。结果：大鼠突触体缺血状态致游离钙浓度、门冬氨酸和甘氨酸、牛磺酸、γ-氨基丁酸释放量明显增加，而谷氨酸亦有增加趋势。缺血 + 50 mmol/L 高钾刺激后，游离钙浓度及上述EAA及IAA释放量均进一步增加。10-4 mol/L Nifedipine可明显降低两种状态下缺血突触体内游离钙浓度，同时亦显著阻遏静息状态缺血突触体IAA的释放及去极化状态EAA和IAA的释放。结论：Nifedipine的抗脑缺血致脑损伤作用主要与其对抗缺血引起的突触体内游离钙浓度升高有关，其抑制EAA和IAA释放与脑缺血保护作用的关系有待进一步研究。

Preparation of Sustained-release Silybin Microspheres by Spherical Crystallization Technique

Aim To improve the dissolution rate and bioavailability of silybin. Methods Sustained-release silybin microspheres were prepared by the spherical crystallization technique with soliddispersing and release-retarding polymers. A differential scanning calorimeter and an X-ray diffractometer were used to investigate the dispersion state of silybin in the microspheres. The shape, surface morphology, and internal structure of the microspheres were observed using a scanning electron microscope. Characterization of the microspheres, such as average diameter, size distribution and bulk density of the microspheres was investigated. Results The particle size of the microspheres was determined mainly by the agitation speed. The dissolution rate of silybin from microspheres was enhanced by increasing the amount of the dispersing agents, and sustained by the retarding agents. The release rate of microspheres was controlled by adjusting the combination ratio of the dispersing agents to the retarding agents. The resuits of X-ray diffraction and differential scanning calorimetry analysis indicated that silybin was highly dispersed in the microspheres in amorphous state. The release profiles and content did not change after a three-month accelerated stability test at 40 ℃ and 75% relative humidity. Conclusion Sustained-release silybin microspheres with a solid dispersion structure were prepared successfully in one step by a spherical crystallization technique combined with solid dispersion technique. The preparation process is simple, reproducible and inexpensive. The method is efficient for designing sustained-release microspheres with water-insoluble drugs.

Bay K8644及nifedipine对大鼠下丘脑神经元L-型Ca^(2+)通道特性的影响

采用神经元急性分离和膜片箝技术以及细胞贴附式方式记录通道活动 ,探讨DHP类Ca2 +通道激动剂BayK8644及拮抗剂nifedipine对下丘脑神经元L 型Ca2 +通道的影响。结果显示 ,在BayK8644作用下 ,通道开放形式发生变化 ,明显可见多级开放 ;通道平均开放时间、平均开放概率显著增加 ,但单通道电导无明显变化。nifedipine的作用与BayK8644相反。结果提示 ,BayK8644对下丘脑神经元L 型Ca2 +通道有明显激动作用 ,nifedip

Pharmacokinetics and Relative Bioavailability ofsustained-release Tablets of Diclofenac Sodiumin Male Volunteers

The pharmacokinetics of a sustained- release formulation and an enteric- coated tablet of diclofenac sodium were studied on 8 healthy male volunteers in an open,randomized crossover study.Drug level in serum was assayed by HPLC method.The changes in serum concentration were conformed to a l-compartment open model.The t_1/2 (Ke)averaged 2.15±0.17 and ll.60 ± l.95 h,and the areas under the drug concentration curves were 5.87 ± 0.67 and 5.55 ± 0.57μgh/ml for enteric-coated and sustained-release tablet of diclofenac sodium,respectively. The mean relative bioavailability of sustained-release tablet was 0.95 to that of enteric-coated tablet.

DHEA和nifedipine对大鼠低氧性肺动脉高压的治疗作用比较

目的 对慢性缺氧3周大鼠静脉注射钾通道开放剂脱氢表雄甾酮(DHEA)和钙通道阻断剂nifedipine,以对照研究它们对大鼠慢性低氧性肺动脉高压的治疗作用。方法 60只大鼠随机分为2组,每组30只,均给予缺氧3周。Ⅰ组再分为3个小组(A1,A2,A3),分别按100mg/kg,150mg/kg和200mg/kg给予DHEA,Ⅱ组再分为3个小组(B1,B2,B3),按100mg,/kg,150mg/kg和200mg,/kg给予nifedipine。大鼠3周低氧后,行右心插管于给药前后分别测定2组大鼠的肺动脉平均压(mPAP)、体动脉平均压(mSAP)。结果 2组大鼠在缺氧3周后肺劝脉压均明显增高,Ⅰ组静脉给予DHEA可见A1,A2,A3组大鼠mPAP明显降低,呈剂量依赖性变化,但平均体动脉压变化不明显;Ⅱ组给予nifedipine后,可见B1,B2,B3组大鼠伴随mSAP明显降低,大鼠mPAP呈剂量依赖性降低。结论 钾通道活性的改变在HPH发病机制中起着十分重要的作用,钾通道开放剂DHEA可有效治疗HPH,且DHEA对体循环的影响相对较小。

Influence of Preparation Factors on the Sustained Release of Nifedipine from Eudragit RL/RS Microspheres

Sustained release Eudragit RL/RS microspheres encapsulating nifedipine were prepared using the acetone/liquid paraffin emulsion solvent evaporation method. The influence of different preparation factors on release of the drug in vitro was investigated. The release rate of nifedipine from the microspheres increased with increasing Eudragit RL/RS ratio and stirring rate during the preparation, and with decreasing the polymer concentration of internal phase and microsphere size. It was found that a linear relationship existed between the microsphere size and the time of 50% drug release. The drug release rate increased with increasing nifedipine content from 4.2 to 16.7% and was more rapid than the dissolution rate of pure nifedipine particles. However, the release rate of the microspheres with 26.6% drug content decreased significantly and was slower than the dissolution rate of pure drug particles. This was attributed mainly to the nifedipine dispersion state in the microspheres as confirmed by the differential thermal analysis and X ray diffraction study, which showed that nifedipine was present in an amorphous or molecular state in the microspheres with 4.2, 9.4 and 16.7% drug, whereas partly in the crystalline state in the microspheres with 26.6% drug. The amounts released for less than 70% nifedipine can be fitted to Higuchi square root of time model, independent of polymer ratio, drug content and microsphere size.

Development and characterization of ethylcellulose based microsphere for sustained release of nifedipine

This article introduced the work of ethylcellulose based polymeric microsphere loaded with nifedipine for reduction in frequency of administration with low solubility in aqueous medium and high rate of absorption in the stomach. The non-aqueous polymeric suspension was put dropwise into an aqueous medium containing polyvinyl alcohol as a surfactant for the synthesis of microsphere by solvent evaporation. The microspheres were characterized by different techniques, namely, XRD, SEM, and NMR. The formation of microspheres was confirmed by SEM. XRD analysis revealed the semi-crystallinity nature of microspheres. The NMR study indicated the presence of hetero-aromatic nucleus in the microsphere.

Methylprednisolone microsphere sustained-release membrane inhibits scar formation at the site of peripheral nerve lesion

Corticosteroids are widely used for the treatment of acute central nervous system injury. However, their bioactivity is limited by their short half-life. Sustained release of glucocorticoids can prolong their efficacy and inhibit scar formation at the site of nerve injury. In the present study, we wrapped the anastomotic ends of the rat sciatic nerve with a methylprednisolone sustained-release membrane. Compared with methylprednisone alone or methylprednisone microspheres, the methylprednisolone microsphere sustained-release membrane reduced tissue adhesion and inhibited scar tissue formation at the site of anastomosis. It also increased sciatic nerve function index and the thickness of the myelin sheath. Our findings show that the methylprednisolone microsphere sustained-release membrane effectively inhibits scar formation at the site of anastomosis of the peripheral nerve, thereby promoting nerve regeneration.

Properties of Aroma Sustained-release Cotton Fabric with Rose Fragrance Nanocapsule

The aroma sustained-release cotton fabric was prepared by finishing rose fragrance nanocapsules directly on cotton.The structure and properties of nanocapsules were demonstrated by transmission electron microscope(TEM),dynamic light scattering(DLS),fourier transform infrared spectrometer(FTIR),X-ray diffraction (XRD),gas chromatography-mass spectrometry(GC-MS)and electronic nose.The results showed that the spherical nanocapsule dispersed evenly and the average diameter kept 51.4 nm.The existence of COO peak(1741 cm? 1)in the FTIR curve of the finished cotton fabric and the decrease of crystallinity demonstrated that rose fragrance nanocapsules have been incorporated into the cotton fabrics.The washing resistance of the cotton fabrics finished by 51.4 nm nanocapsules was much better than that by rose fragrance alone.Besides,the loss of fragrance from the cotton fabrics finished by 51.4 nm nanocapsules was obviously lower than that by 532 nm nanocapsules and rose fragrance.The smaller the nanocapsule size,the better the sustained release property.Electronic nose analysis also displayed that the aroma released from the cotton fabrics finished by nanocapsules after washing has no obvious variety in contrast to that without washing.The cotton fabrics finished by nanocapsules has the excellent sustained release property.

Release performance and sustained-release efficacy of emamectin benzoate-loaded polylactic acid microspheres

High-performance liquid chromatography （HPLC） was employed to determine drug release rates based on emamectin benzoate concentrations in the medium. Release kinetics equations were used to fit the drug release behavior. The effects of particle size and release medium pH on the release rate were also investigated. The indoor toxicity of emamectin benzoate-loaded polylactic acid microspheres on the diamondback moth larva （Plutella xylostella） was studied to explore drug sustained-release performance. In acidic and neutral media, the drug release behavior of the microspheres was in accord with the first-order kinetics equation. Increasing the spray dosage of emamectin benzoate-loaded polylactic acid microspheres initially resulted in an equivalent insecticidal efficacy with the conventional emamectin benzoate microemulsion. However, the drug persistence period was four-fold longer than that observed using the conventional formulation. The developed emamectin benzoate-loaded polylactic acid microspheres showed dramatic sustained-release performance. A treatment threshold of greater than 35 mg mL-1 was established for an efficient accumulated release concentration of emamectin benzoate-loaded microspheres.

The preparation and the in-vitro pharmacodynamics study of the intracapsular sustained-release preparations for the prevention of posterior capsule opacification

Docetaxel-loaded sustained-release preparation based on 2-Hydroxyethyl methacrylate(HEMA)and Methyl methacrylate(MMA)cross-linked copolymer(P(HEMA-co-MMA))was prepared to examine the potential use for preventing posterior capsule opacification(PCO).The preparations were prepared by polymerizing the mixture of HEMA,MMA,cross-linking agent(EGDMA),initiator(AIBN)and docetaxel.The influence factors and mechanism of drug release were studied in the experiments.FT-IR,X-RD and SEM methods were used to characterize the polymer(P(HEMA-co-MMA))and docetaxel-loaded sustained-release preparations.Biocompatibility of P(HEMA-co-MMA)and in-vitro effect of docetaxel-loaded sustained-release preparations were also evaluated.The results showed that docetaxel could release sustainedly from these preparations prepared by cross-linking polymerization.And the release rate could be accelerated by increasing the MMA ratio or EGDMA ratio of the polymer.Release mechanism of docetaxel fitted the Higuchi model well.The results of IR and X-RD showed that only a hydrogen bond was formed between docetaxel and P(HEMA-co-MMA).Docetaxel dispersed in P(HEMA-co-MMA)in amorphous form.The elution test showed that P(HEMA-co-MMA)had good biocompatibility and the in-vitro pharmacodynamics study proved that docetaxel could release stably from the preparations and inhibit HLECs’proliferation.The docetaxel-loaded sustained-release preparations proved to be a promising therapy for preventing PCO.These results also lay a theoretical and experimental foundation for the future.

Improving Flow Property of Nifedipine Loaded Solid-Lipid Nanoparticles by Means of Silica for Oral Solid Dosage Form

In this study, a new formulation of silica nanocomposite containing nifedipine (NI) loaded freeze-dried solid-lipid nanoparticles (NI-SLNs) and silica have been developed with improved flowability of powders, which can lead to the formulation of a widely acceptable oral dosage form. The stable NI-SLNs were prepared using two phospholipids, hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol mixed with 2.5% w/v trehalose as a cryoprotectant followed by lyophilization. We employed various grades of two types of silica, such as fumed and precipitated. Silica improved the poor flow property of NI-SLNs to good category as per USP-29. In addition, most of the silica nanocomposites showed the satisfactory results in their physicochemical properties such as particle size, polydispersity index, zeta potential, and recovered potency by around 100 nm, 0.3, -50 mV, and 80%, respectively. Furthermore, it was found that NI-SLNs were easily released form nanocomposites within 30 min, therefore, suggesting an improvement of drug dissolutions. Among them, precipitated silica cooperated fairly in improving the powder characteristics as well as the physicochemical, morphological, and pharmaceutical properties.

Tunable and sustained-release characteristics of venlafaxine hydrochloride from chitosan–carbomer matrix tablets based on in situ formed polyelectrolyte complex film coating

The objective of this study is to design sustained-release tablets using matrix technology, which can well control the release of highly water-soluble drugs with good system robustness and simple preparation process. Taking venlafaxine hydrochloride(VH) as a drug model, the feasibility of using chitosan(CS), carbomer(CBM) combination system to achieve this goal was studied. Formulation and process variables influencing drug release from CS–CBM matrix tablets were investigated. It was found that CS–CBM combination system weakened the potential influence of CS, CBM material properties and gastric emptying time on drug release profile. Demonstrated by direct observation, differential scanning calorimetry(DSC) and Fourier transform infrared spectroscopy(FTIR), in situ self-assembled polyelectrolyte complex(PEC) film was formed on the tablet surface during gastrointestinal tract transition, which contributed to the tunable and robust control of drug release. The sustained drug release behavior was further demonstrated in vivo in Beagle dogs, with level A in vitro and in vivo correlation(IVIVC) established successfully. In conclusion, CS–CBM matrix tablets are promising system to tune and control the release of highly water-soluble drugs with good system robustness.

Evaluation Procedure for Quality Consistency of Generic Nifedipine Extended-Release Tablets Based on the Impurity Profile

A procedure to evaluate the quality consistency of generic drugs based on the impurity profile and the similarity analysis methods was presented in this paper. Nifedipine extended-release tablets from six generic factories of China were used to evaluate the uniformity with the original drug in the study. The procedure includes: choice of chromatographic methods, data collection and conformity test, evaluation of intra-batch similarity of drugs, evaluation of generic drugs with the original drug and weighted similarity evaluation of generic drugs. The data were collected via high-performance liquid chromatography (HPLC), and then calculated by correlation coefficient, cosine, principal component analysis (PCA) and hierarchical clustering analysis (HCA). It is more suitable to use peak areas as the vector when calculating the similarity of impurity profile. After weighting the peak areas of the unspecified impurities in further evaluation of the generic quality, the generic level of different factories was differentiated and the best generic factory was picked out.

Preparation and evaluation of tamsulosin hydrochloride sustained-release pellets modified by two-layered membrane techniques

The aim of the present study was to develop tamsulosin hydrochloride sustained-release pellets using two-layered membrane techniques.Centrifugal granulator and fluidizedbed coater were employed to prepare drug-loaded pellets and to employ two-layered membrane coating respectively.The prepared pellets were evaluated for physicochemical characterization,subjected to differential scanning calorimetry(DSC)and in vitro release of different pH.Different release models and scanning electron microscopy(SEM)were utilized to analyze the release mechanism of Harnual■ and home-made pellets.By comparing the dissolution profiles,the ratio and coating weight gain of Eudragit■ NE30D and Eudragit■ L30D55 which constitute the inside membrane were identified as 18:1 and 10%-11%.The coating amount of outside membrane containing Eudragit■ L30D55 was determined to be 0.8%.The similarity factors(f_(2))of home-made capsule and commercially available product(Harnual■)were above 50 in different dissolution media.DSC studies confirmed that drug and excipients had good compatibility and SEM photographs showed the similarities and differences of coating surface between Harnual■ and self-made pellets before and after dissolution.According to Ritger-Peppas model,the two dosage form had different release mechanism.

Aggressive treatment of acute anal fissure with 0.5% nifedipine ointment prevents its evolution to chronicity

AIM： To investigate the efficacy of topical application of 0.5% nifedipine ointment in healing acute anal tissue and preventing its progress to chronicity. METHODS： Thirty-one patients （10 males, 21 females） with acute anal fissure from September 1999 to January 2005 were treated topically with 0.5% nifedipine ointment （t.i.d.） for 8 wk. The patients were encouraged to follow a high-fiber diet and assessed at 2, 4 and 8 wk post-treatment. The healing of fissure and any side effects were recorded. The patients were subsequently followed up in the outpatient clinic for one year and contacted by phone every three months thereafter, while they were encouraged to come back if symptoms recurred. RESULTS： Twenty-seven of the 31 patients completed the 8-wk treatment course, of them 23 （85.2%） achieved a complete remission indicated by resolution of symptoms and healing of fissure. Of the remaining four unhealed patients （14.8%）, 2 opted to undergo lateral sphincterotomy and the other 2 to continue therapy for four additional weeks, resulting in healing of fissure. All the 25 patients with complete remission had a mean follow-up of 22.9 ± 14 （range 6-52） too. Recurrence of symptoms occurred in four of these 25 patients （16%） who were successfully treated with an additional 4-wk course of 0.5% nifedipine ointment. Two of the 27 （7.4%） patients who completed the 8-wk treatment presented with moderate headache as a side effect of nifedipine. CONCLUSION： Topical 0.5% nifedipine ointment, used as an agent in chemical sphincterotomy, appears to offer a significant healing rate for acute anal fissure and might prevent its evolution to chronicity.