Evaluation of Monolithic Osmotic Tablet System for Nifedipine Delivery In Vitro and In Vivo

Abstract

The aim of this study was to evaluate the monolithic osmotic tablet system (MOTS) containing a solid dispersion with the practically water-insoluble drug nifedipine in vitro and in vivo. In the drug release study in vitro, the release profiles of this system had almost zero-order kinetics. The influences of tablet formulation variables, sizes of the delivery orifice, membrane variables, and values of pH in the dissolution medium on nifedipine release from MOTS have been investigated. The results provided evidence that the tablet core played an important role in MOTS. While orifice sizes and membrane variables affected the nifedipine release rate, MOTS was independent of the dissolution medium. The appropriate orifice size was found to be in the range of 0.5–1.0 mm. The coating membrane incorporating hydrophilic polyethylene glycol (PEG) formed a porous structure. The human pharmacokinetics and relative bioavailability of MOTS containing nifedipine were compared with a commercial Adalat® osmotic tablet system containing an equivalent dose of nifedipine following an oral single dose of 30 mg given to each of 11 healthy volunteers in an open, randomized crossover study in vivo. The relative bioavailability for MOTS was 112%. There was no statistically significant difference in the pharmacokinetic parameters between two dosage forms. It is concluded that the monolithic osmotic tablet controlled release system is feasible for a long-acting preparation as a once-daily treatment.     

Development of Monolithic Osmotic Pump Tablet System for Isosorbide-5-Mononitrate Delivery and Evaluation of it In Vitro and In Vivo

The objective of this study is to develop the monolithic osmotic pump tablet system (MOTS) containing isosorbide-5-mononitrate (5-ISMN), and to evaluate its in vitro and in vivo properties. The influences of tablet formulation variables, size and location of the delivery orifice, membrane variables, and pH value of the dissolution medium on 5-ISMN release from MOTS have been investigated. These results demonstrated that the tablet core played an important role in MOTS, and membrane variables could affect the 5-ISMN release rate. The optimal formulation of 5-ISMN MOTS was determined by uniform design. Furthermore, the dog pharmacokinetics and relative bioavailability of the test formulation (5-ISMN MOTS) have been compared with the reference formulation (Imdur^®: 60 mg/tablet, a sustained release, SR, tablet system) following an oral single dose of 60 mg given to each of six Beagle dogs. The mean drug fraction absorbed by the dog was calculated by the Wagner–Nelson technique. The results showed that drug concentration in plasma could be maintained more stable and longer after the administration of 5-ISMN MOTS compared with the matrix tablets of Imdur^®, and a level A “in vitro–in vivo correlation” was observed between the percentage released in vitro and percentage absorbed in vivo. It is concluded that 5-ISMN MOTS is more feasible for a long-acting preparation than 5-ISMN SR tablet system as once-a-day treatment, and it is very simple in preparation, and can release 5-ISMN at the rate of approximately zero order for the combination of hydroxypropylmethyl cellulose as retarder and NaCl as osmogent.     

Investigations of a Novel Self-Emulsifying Osmotic Pump Tablet Containing Carvedilol

Carvedilol has been made into a novel osmotic pump tablet which includes Gelucire 44/14, Lutrol F68, Transcutol P, silicon dioxide, mannitol, citric acid, and sodium hydrogen carbonate. The Self-emulsifying osmotic pump tablet (SEOPT) has two outstanding features. It could improve the bioavailability of carvedilol by self-emulsifying drug delivery system (SEDDS), control the release rate and make the plasma concentrations more stable by elementary osmotic pump tablet. The results of transmission electron microscope (TEM) and particle size assessment showed that the shape of the resultant emulsion was round and regular, the average diameter of the particles was 246 nm. Since the solubility of carvedilol was improved by the emulsion, the elementary SEOPT could guarantee a complete release of carvedilol under the osmotic pressure of mannitol. The cumulative release at 12 hr was 85.18%. Therefore the disadvantage that lipophilic drugs can not be released completely when prepared into elementary osmotic pump tablet was resolved. The results of Differential scanning calorimetry (DSC), Infrared spectroscopy (IR) and X-ray diffraction diffraction (XRD) proved that carvedilol was amorphous in the preparation. The relative bioavailability of carvedilol in beagle dogs was 156.78%. The plasma concentrations were more stable compared with that of commercially available tablet (Luode®). And the in vitro and in vivo correlation was good (r = 0.9725). Therefore, the elementary SEOPT developed in this paper might provide a new idea for preparing lipophilic drugs into osmotic pump tablet conveniently.     

固体颗粒的分散

详细阐述了固体颗粒分散的原理及实践。指出了颗粒分散研究所存在的问题和解决的办法。     

电喷雾法制备药物-高分子固体分散体

以灰黄霉素（GRIS）-聚乙烯吡咯烷酮（PVP）体系为例,研究了电喷雾法制备药物-高分子固体分散体,并采用偏光显微镜（POM）、X射线衍射仪（XRD）和差示扫描量热仪（DSC）等方法对体系进行表征。电喷雾法制备得到的微米级固体分散体样品中,体系玻璃化转变温度,很好地符合半经验公式Fox方程,说明GRIS在体系中分散均匀...     

粒料法合成高固含量聚氨酯分散体胶粘剂

以聚己二酸1,4-丁二醇酯(PBA-3000)为软段、异佛尔酮二异氰酸酯(IPDI)、1,4-丁二醇(BG)为硬段、聚醚二元醇磺酸盐(SPPG)作为亲水单体,采用本体聚合方法合成了聚氨酯离子聚合物。聚氨酯离子聚合物经造粒、丙酮溶解、水分散、去丙酮得到固含量为50%的高固含量聚氨酯分散体胶粘剂。研究了硬段含量、分子量对分散体平均粒径和粒径分布、胶膜的热学性能以及粘合性能的影响。聚氨酯分散体胶粘剂的最高初粘力为6N/mm,最高剥离强度为10.24 N/mm。     

HDI-IPDI型高固含量水性聚氨酯分散体的合成及微观形态

以预聚体分散法合成了固含量达50%的高固含量水性聚氨酯分散体.研究了影响高固含量水性聚氨酯分散体的黏度、粒径、粒径分布及粒子微观形态的因素.结果表明,随着DMPA含量、HDI/IPDI摩尔比及软段分子量(M)n的增加,乳液的黏度增大,粒径减小.粒径分布随着DMPA含量及PBA分子量的增加而变窄,HDI/IPDI对粒径分布的影响较小;在DMPA含量较低或者PBA分子量在2000以下时获得的分散体具有较广的粒径分布.此外,分散液还呈现出二元粒径分布趋势.透射电镜对胶束形态研究表明,随着软段分子量的增加,胶束呈现出聚集趋势,并且随着DMPA含量的增加,聚集更紧密.     

固体环氧树脂水分散体的制备和性能

用中等分子量的固体双酚A型环氧树脂ER-1和环氧乙烷/环氧丙烷的嵌段共聚物Lutrol F68合成了一种活性非离子型乳化剂F68-E,对乳化剂F68-E的结构以及合成过程进行了分析。用乳化剂F68-E对环氧树脂ER-1进行乳化,探讨了使用相反转法乳化时,乳化剂浓度、乳化温度和溶剂种类对环氧树脂水分散体的粒径和力学稳定性的影响。此外,将环氧树脂水分散体制成中温固化体系,对其干膜固化物进行了吸水率测试和动态热机械分析。结果表明,引入12%的乳化剂F68-E后,固化体系的吸水率由1.38%降至0.97%,玻璃化转变温度由102.5℃降至82.6℃。     

Controlled release of ziprasidone solid dispersion systems from osmotic pump tablets with enhanced bioavailability in the fasted state

Objective: The purpose of this work was to develop a controlled release of ziprasidone with no food effect by the osmotic release strategy.

Methods: The solution of ziprasidone and poloxamer188 (P188) with different weight ratios was spray-dried to form solid dispersion of ziprasidone (SD-ZIP). The SD-ZIP was characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (X-RD) and solubility testing. The SD-ZIP osmotic pump tablets were prepared by wet granulation method. The effect of formulation variables on the release characteristic was investigated. The SD-ZIP osmotic pump tablets were administered to fasted and fed beagle dogs and their pharmacokinetics were compared to commercial formulation Zeldox® as a control.

Results: The results of DSC and X-RD indicated that ziprasidone resides in P188 with no crystalline changes. Solubility studies demonstrated that the solubility of SD-ZIP was substantially improved compared to ziprasidone and physical mixtures of ziprasidone and P188. The optimized formulation and drug release profiles of SD-ZIP osmotic pump tablets in different medium were obtained which showed typical osmotically controlled release and could fitted to zero-order kinetics with good linear correlation. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolong actions and no food effect was achieved simultaneously in SD-ZIP osmotic pump tablet compared with Zeldox®.

Conclusion: The SD-ZIP osmotic pump tablet could be able to enhance the bioavailability in the fasted state and showed sustained release with prolonged actions.     

Preparation,Characterization and In Vitro Evaluation of Solid Dispersions Containing Docetaxel

Solid dispersions using water-soluble carriers were studied for improving the dissolution of docetaxel, a poorly soluble compound. In order to obtain the most optimized formulation, we prepared many solid dispersions with different carriers, different solvents, or at a series of drug-to-carrier ratios, and compared their dissolution. The accumulative dissolution of docetaxel from poloxamer 188 was more excellent than that from PVP_k30 and glyceryl monostearate, and the dissolution of docetaxel from solid dispersion was markedly higher than that of pure docetaxel; meanwhile the increased dissolution was partly dependent on the ratios of docetaxel and poloxamer 188. The ethanol used to prepare solid dispersion is of more significant effect on the dissolution of docetaxel than that of acetone. The docetaxel/poloxamer 188 system was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and environmental scanning electron microscope (ESEM). The results of DSC, XRD, and ESEM analyses of docetaxel/poloxamer 188 system showed that there are intermolecular interactions between docetaxel and poloxamer, and the crystallinity of docetaxel disappeared. These results show that solid dispersion is a promising approach of developing docetaxel drug formulates.     

7-Ethyl-10-hydroxycamptothecin proliposomes with a novel preparation method: optimized formulation,characterization and in-vivo evaluation

Context:?The proliposomes were used to solve the stability of the ordinary liposomes. Objective: 7-ethyl-10-hydroxycamptothecin (SN-38) proliposomes for intravenous (i.v.) administration were prepared successfully by a new method.

Materials and methods:?SN-38 liposomes solution was reconstituting automatically from proliposomes on contact with the acetic acid buffer solution (0.2 M, pH 2.6). The formulation was optimized by the Box–Behnken design. The physicochemical characteristics of the SN-38 proliposomes were studied by scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The stability studies were also carried on. The FLU–HPLC system was served to study the concentration of SN-38 in the plasma of Sprague Dawley (SD) rats.

Results:?The optimized formulation was SN-38: 0.03 g; Soybean phospholipid (SP): 0.6 g; dextrose: 3.00 g. The entrapment efficiency of the optimized formulation was >85% and the mean particle size was about 231 nm. The stability studies showed that SN-38 proliposomes were stable in dark at 20–25°C for 6 months at least. The pharmacokinetic parameters of i.v. administration demonstrated that the half-life of SN-38 loaded in the liposomes was prolonged in vivo.

Discussion and conclusion:?The SN-38 proliposomes was prepared successful by the analysis of TEM, SEM, DSC and XRD, and SN-38 liposomes could be reconstituted on contact with the hydration medium. SN-38 liposomes circulated for a longer time in the blood circulating system than SN-38 solution, which contributed to maintaining the drug action.     

Enhancing the Bioavailability of Cyclosporine A Using Solid Dispersion Containing Polyoxyethylene (40) Stearate

ABSTRACT

Solid dispersion containing polyoxyethylene (40) stearate and cyclosporine A was prepared by solvent-melt method and characterized using differential scanning calorimetry, powder X-ray diffraction, and Infrared Fourier Transform Spectroscopy (FTIR). Dissolution of the drug from solid dispersion was dramatically enhanced compared to that from the drug powder alone and physical mixture. In vivo oral bioavailability of cyclosporine A from the solid dispersion in Wistar rats was comparable to that from a commercial product, Sandimmun Neoral® (P > 0.05). The formulation is stable up to six months under 30°C/RH60% and one year at 25°C/RH 60% when packed in aluminum-polyethylene laminated bags.     

Dispersion of Axisymmetric Longitudinal Waves in A Bi-Material Compound Solid Cylinder Made of Viscoelastic Materials

The paper studies the dispersion of axisymmetric longitudinal waves in the bi-material compound circular cylinder made of linear viscoelastic materials. The investigations are carried out within the scope of the piecewise homogeneous body model by utilizing the exact equations of linear viscoelasto-dynamics. The corresponding dispersion equation is derived for an arbitrary type of hereditary operator and the algorithm is developed for its numerical solution. Concrete numerical results are obtained for the case where the relations of the constituents of the cylinder are described through fractional exponential operators. The influence of the viscosity of the materials of the compound cylinder on the wave dispersion is studied through the rheological parameters which indicate the characteristic creep time and long-term values of the elastic constants of these materials. Dispersion curves are presented for certain selected dispersive and non-dispersive attenuation cases under various values of the problem parameters and the influence of the aforementioned rheological parameters on these curves is discussed. As a result of the numerical investigations, in particular, it is established that in the case where the rheological parameters of the components of the compound cylinder are the same, the viscosity of the layers' materials causes the axisymmetric wave propagation velocity to decrease.     

Preparation of a Solid Dispersion by a Dropping Methodto Improve the Rate of Dissolution of Meloxicam

Application of a solid dispersion system is one of the methods used to increase the bioavailability of poorly water-soluble drugs. Adaptation of the dropping method from the chemical industry as a formulation procedure may help the scaling-up process and simplify the formulation of poorly water-soluble compounds. Meloxicam (ME), a nonsteroidal anti-inflammatory drug that is poorly soluble in water, and polyethylene glycol (PEG) 4000, a water-soluble carrier, were formulated by using a dropping method in an attempt to improve the dissolution of ME. Pure ME and physical mixtures and tablets of ME–PEG 4000 (1:3 ratio) were compared as regards their dissolution with samples formulated by the dropping method. The results revealed that the round particles (solid drops) exhibited a higher dissolution rate than those of the physical mixtures, tablets, and pure ME. Self-modeling curve resolution (SMCR) as a chemometric method was used to evaluate X-ray powder diffractometry (XRPD) data. The results demonstrated the presence of a new crystalline phase in the solid dispersion, which can help the fast and quantitative dissolution from the solid drops. The round particles can be adapted to individual therapy by using a distributor.     

固-液-固3层结构板中超声兰姆波的频散特性

文章采用传统矩阵方法研究固－液－固3层结构板中兰姆波的传播,数值计算结果证明了用该方法分析层状材料中的兰姆波的有效性与实用性,文章计算出的多种频散曲线对超声兰姆波的应用是有益的。     

Zinc‐Tiered Synthesis of 3D Graphene for Monolithic Electrodes

A high‐surface‐area conductive cellular carbon monolith is highly desired as the optimal electrode for achieving high energy, power, and lifetime in electrochemical energy storage. 3D graphene can be regarded as a first‐ranking member of cellular carbons with the pore‐wall thickness down to mono/few‐atomic layers. Current 3D graphenes, derived from either gelation or pyrolysis routes, still suffer from low surface area, conductivity, stability, and/or yield, being subjected to methodological inadequacies including patchy assembly, wet processing, and weak controllability. Herein, a strategy of zinc‐assisted solid‐state pyrolysis to produce a superior 3D graphene is established. Zinc unprecedentedly impregnates and delaminates a solid (“nonhollow”) char into multiple membranes, which eliminates the morphological impurities ever‐present in the previous pyrolyses using solid‐state carbon precursors. Zinc also catalyzes the carbonization and graphitization, and its in situ thermal extraction and recycling enables the scaled‐up production. The created 3D graphene network consists integrally of morphologically and chemically pure graphene membranes. It possesses unrivaled surface area, outstanding stability, and conductivity both in air and electrolyte, exceeding preexisting 3D graphenes. The advanced 3D graphene thus equips a porous monolithic electrode with unparalleled energy density, power density, and lifetime in electric‐double‐layer capacitive devices.     

Preparation and Characterization of 10-Hydroxycamptothecin Loaded Nanostructured Lipid Carriers

Two types of 10-hydroxycamptothecin (10-HCPT) loaded nanostructured lipid carriers (NLC-F 68 and NLC-Brij 35) intended for use as the alternative formulation of 10-HCPT for parenteral administration were prepared using an emulsification-ultrasonication method and fully characterized from physicochemical and in vitro release standpoint. The particle size was measured by laser diffraction, being 108 nm and 126 nm for NLC-F 68 and NLC-Brij 35, respectively. Zeta potentials of two NLCs were ?28.5 mV and ?32.1 mV analyzed by photon correlation spectroscopy. The incorporated efficiency was more than 85%. It is observed that NLCs are homogeneous and spherical in shape by transmission electron microscopy. Differential scanning calorimetry analysis of NLCs showed that 10-HCPT was dispersed within NLC in an amorphous state. The combination of trehalose and mannitol as cryoprotectant was most suitable for HCPT-NLC lyophilization. The in vitro release behavior for two types of NLC was similar and displayed biphasic drug release pattern with rapid release at the initial stage and prolonged release afterwards. These results suggest that NLC could be exploited as a carrier of 10-HCPT with high incorporation efficiency and controlled release and that NLC may serve as the alternative delivery system for parenteral administration of 10-HCPT.     

Application of scCO2 technology for preparing CoQ10 solid dispersion and SFC-MS/MS for analyzing in vivo bioavailability

Objective: In this study, solid dispersion (SD) for oral delivery of a poorly water-soluble drug, coenzyme Q10 was developed by supercritical fluid technology and characterized in vitro and in vivo.

Methods: Dissolution was used to optimize the formulations of CoQ10-SD. The physicochemical properties of SD were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The supercritical fluid chromatography–electrospray ionization tandem mass spectrometry (SFC–ESI-MS/MS) was used for the in vivo study.

Results: The results of DSC and PXRD indicated that the drug in SD was in amorphous state. In vitro drug release, the dissolution of coenzyme Q10 in solid dispersion improved to 78.8% compared with commercial tablets of 0.16%. The area under c–t curve (AUC_0–72h) and mean maximum concentrations (C_max) of CoQ10-SD were 2.43-fold and 3.0-fold, respectively higher than that of commercial tablets in rats, confirming improved bioavailability.

Conclusion: Supercritical fluid technology was successfully used for the preparation and analysis of CoQ10-SD for the first time and significantly improved the dissolution and bioavailability of coenzyme Q10.     

基于二聚酸多元醇的高固含量聚氨酯分散体的合成及乳液性能

以二聚酸二元醇、二羟甲基丙酸(DMPA)、三羟甲基丙烷(TMP)、异佛二酮二异氰酸酯(IPDI)、三乙胺(TEA)、乙二胺(EDA)为原料,采用预聚直接分散法合成了固含量50%以上的聚氨酯分散体(PUD)。研究结果表明,PUD平均粒径多为100 nm~110nm,粒径多分布于50 nm~200nm范围内,羧基和TMP含量的增加使胶粒粒径变小。透射电镜(TEM)表征显示分散体胶粒呈多分散性。PUD的黏度随剪切速率的增加而先增大,随后保持稳定,最后减小。     

Enhanced oral bioavailability of 10-hydroxycamptothecin through the use of poly (n-butyl cyanoacrylate) nanospheres

The article describes the preparation, physicochemical characterization, drug release, and in vivo behavior of 10-hydroxycamptothecin-loaded poly (n-butyl cyanoacrylate) (PBCA) nanospheres (HCPT-PBCA-NSs). HCPT-PBCA-NSs were successfully prepared via emulsion polymerization of n-butyl cyanoacrylate (BCA) monomer in acidic medium with the aid of two colloidal stabilizers (Poloxamer 188 and Dextran 70). The influence of pH, the time of polymerization, and the dosage of the drug on particle size and encapsulation efficiency (EE) were studied. HCPT-PBCA-NSs were of spherical shape and uniformly dispersed with a particle size of 135.7?nm, and zeta potential of ?18.18?mV. EE, drug loading (DL), and yield of HCPT-PBCA-NSs were 51.52, 0.63, and 88.25%, respectively. FTIR, ¹H NMR, and DSC showed complete polymerization of BCA monomer and HCPT existed in the form of molecular or amorphous in NSs. In vitro release of the drug from HCPT-PBCA-NSs exhibited sustained-release behavior with an initial burst release and about 60% of HCPT was released from the formulation within 24?h of dialysis. The pharmacokinetic study in healthy rats after oral administration showed that encapsulation of HCPT into PBCA-NSs increased the C_max about 3.84 times and increased AUC_0?t about 5.40 times compared with that of HCPT suspension. It was concluded that PBCA-NSs could be a promising drug carrier to load HCPT for oral drug delivery if efforts are made in the future to improve its poor DL capacity.