人参总皂苷渗透泵控释片的片芯处方研究

目的:以中药人参的有效部位人参总皂苷为模型药物,进行人参总皂苷渗透泵片的片芯处方研究,以确定其最终片芯处方.方法:采用单因素考察法,从制剂的成型和体外释药特征角度,对人参总皂苷渗透泵片片芯的稀释荆、黏合剂、渗透活性物质和润滑荆进行了筛选.结果:人参总皂苷渗透泵片的最终片心处方为:人参总皂苷提取物100mg,乳糖235mg,淀粉118mg,氯化钠33mg,滑石粉3%～6%.结论:该片心处方辅料来源广泛,利于片心成型,并具有较好的体外释药行为,为人参总皂苷渗透泵控释片的进一步研究打下了基础.     

Development and Optimization of Micro/Nanoporous Osmotic Pump Tablets

Micro/nanoporous osmotic pump tablets coated with cellulose acetate containing polyvinylpyrolidone (PVP) as pore formers were fabricated. Propranolol hydrochloride was used as a model drug in this study. Formulation optimization based on USP 31 requirements was conducted following a central composite design using a two-level factorial plan involving two membrane variables (pore former and coating levels). Effect of molecular weight of pore former (PVP K30 and PVP K90) was also evaluated. Responses of drug release to the variables were analyzed using statistical software (MINITAB 14). Scanning electron microscopy and atomic force microscopy showed that the pores formed by PVP. The drug release was dependent on the molecular weight and concentration of PVP and the level of coating. The results showed that acceptable 12-h profile could be achieved with only specific range of PVP K30-containing membrane at the defined membrane thickness. However, satisfactory 24-h profile could be accomplished by both PVP K30 and PVP K90-containing membrane at the range and membrane thickness tested. Preparation and testing of the optimized formulation showed a good correlation between predicted and observed values.     

Development and <Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Etodolac Controlled Porosity Osmotic Pump Tablets

The aim of the current work was the design and evaluation of etodolac controlled porosity osmotic pump (CPOP) tablets exhibiting zero-order release kinetics. Variables influencing the design of (1) core tablets viz., (a) osmogent type (sodium chloride, potassium chloride, mannitol, and fructose) and (b) drug/osmogent ratio (1:0.25, 1:0.50, and 1:0.75), and (2) CPOP tablets viz., (a) coating solution composition, (b) weight gain percentage (1–5%, w/w), and (c) pore former concentration (5%, 10%, and 20%, v/v), were investigated. Statistical analysis and kinetic modeling of drug release data were estimated. Fructose-containing core tablets showed significantly (P < 0.05) more retarded drug release rates. An inverse correlation was observed between drug/fructose ratio and drug release rate. Coating of the optimum core tablets (F4) with a mixture of cellulose acetate solution (3%, w/v), diethyl phthalate, and polyethylene glycol 400 (85:10:5, v/v, respectively) till a 4% w/w weight gain enabled zero-order sustained drug delivery over 24 h. Scanning electron microscopy micrographs of coating membrane confirmed pore formation upon contact with dissolution medium. When compared to the commercial immediate-release Napilac® capsules, the optimum CPOP tablets (F4–34) provided enhanced bioavailability and extended duration of effective etodolac plasma concentration with minimum expected potential for side effects in healthy volunteers.KEY WORDS: cellulose acetate, controlled porosity osmotic pump, etodolac, osmogent, zero order     

Floating Elementary Osmotic Pump Tablet (FEOPT) for Controlled Delivery of Diethylcarbamazine Citrate: a Water-Soluble Drug

The present work investigates the feasibility of the design of a novel floating elementary osmotic pump tablet (FEOPT) to prolong the gastric residence of a highly water-soluble drug. Diethylcarbamazine citrate (DEC) was chosen as a model drug. The FEOPT consisted of an osmotic core (DEC, mannitol, and hydrophilic polymers) coated with a semipermeable layer (cellulose acetate) and a gas-generating gelling layer (sodium bicarbonate, hydrophilic polymers) followed by a polymeric film (Eudragit RL 30D). The effect of formulation variables such as concentration of polymers, types of diluent, and coat thickness of semipermeable membrane was evaluated in terms of physical parameters, floating lag time, duration of floatation, and in vitro drug release. The Fourier transform infrared and X-ray diffraction analysis were carried out to study the physicochemical changes in the drug excipients powder blend. The integrity of the orifice and polymeric film layer was confirmed from scanning electron microscopy image. All the developed FEOPT showed floating lag time of less than 8 min and floating duration of 24 h. A zero-order drug release could be attained for DEC. The formulations were found to be stable up to 3 months of stability testing at 40°C/75% relative humidity.     

Development and Evaluation of Buccoadhesive Controlled Release Tablets of Lercanidipine

The purpose of this research was to develop and evaluate buccal mucoadhesive controlled release tablets of lercanidipine hydrochloride using polyethylene oxide and different viscosity grades of hydroxypropyl methylcellulose individually and in combination. Effect of polymer type, proportion and combination was studied on the drug release rate, release mechanism and mucoadhesive strength of the prepared formulations. Buccal mucoadhesive tablets were made by direct compression and were characterized for content uniformity, weight variation, friability, surface pH, thickness and mechanism of release. In order to estimate the relative enhancement in bioavailability one optimized formulation was evaluated in rabbits. Further, placebo tablets were also evaluated for acceptability in human subjects. Results indicated acceptable physical characteristics of designed tablets with good content uniformity and minimum weight variation. Drug release and mucoadhesive strength were found to depend upon polymer type, proportion and viscosity. The formulations prepared using poly ethylene oxide gave maximum mucoadhesion. The release mechanism of most formulations was found to be of anomalous non-Fickian type. In vivo studies of selected formulation in rabbits demonstrated significant enhancement in bioavailability of lercanidipine hydrochloride relative to orally administered drug. Moreover, in human acceptability studies of placebo formulations, the designed tablets adhered well to the buccal mucosa for more than 4 h without causing any discomfort. It may be concluded that the designed buccoadhesive controlled release tablets have the potential to overcome the disadvantage of poor and erratic oral bioavailability associated with the presently marketed formulations of lercanidipine hydrochloride.     

Release Mechanisms Behind Polysaccharides-Based Famotidine Controlled Release Matrix Tablets

Polysaccharides, which have been explored to possess gelling properties and a wide margin of safety, were used to formulate single-unit floating matrix tablets by a direct compression technique. This work has the aim to allow continuous slow release of famotidine above its site of absorption. The floating approach was achieved by the use of the low density polypropylene foam powder. Polysaccharides (κ-carrageenan, gellan gum, xyloglucan, and pectin) and blends of polysaccharides (κ-carrageenan and gellan gum) and cellulose ethers (hydroxypropylmethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose) were tried to modulate the release characteristics. The prepared floating tablets were evaluated for their floating behavior, matrix integrity, swelling studies, in vitro drug release studies, and kinetic analysis of the release data. The differential scanning calorimetry and Fourier transform infrared spectroscopy studies revealed that changing the polymer matrix system by formulation of polymers blends resulted in formation of molecular interactions which may have implications on drug release characteristics. This was obvious from the retardation in drug release and change in its mechanistics.     

Osmotic Stress Responses and Plant Growth Controlled by Potassium Transporters in Arabidopsis

Osmotic adjustment plays a fundamental role in water stress responses and growth in plants; however, the molecular mechanisms governing this process are not fully understood. Here, we demonstrated that the KUP potassium transporter family plays important roles in this process, under the control of abscisic acid (ABA) and auxin. We generated Arabidopsis thaliana multiple mutants for K⁺ uptake transporter 6 (KUP6), KUP8, KUP2/SHORT HYPOCOTYL3, and an ABA-responsive potassium efflux channel, guard cell outward rectifying K⁺ channel (GORK). The triple mutants, kup268 and kup68 gork, exhibited enhanced cell expansion, suggesting that these KUPs negatively regulate turgor-dependent growth. Potassium uptake experiments using ⁸⁶radioactive rubidium ion (⁸⁶Rb⁺) in the mutants indicated that these KUPs might be involved in potassium efflux in Arabidopsis roots. The mutants showed increased auxin responses and decreased sensitivity to an auxin inhibitor (1-N-naphthylphthalamic acid) and ABA in lateral root growth. During water deficit stress, kup68 gork impaired ABA-mediated stomatal closing, and kup268 and kup68 gork decreased survival of drought stress. The protein kinase SNF1-related protein kinases 2E (SRK2E), a key component of ABA signaling, interacted with and phosphorylated KUP6, suggesting that KUP functions are regulated directly via an ABA signaling complex. We propose that the KUP6 subfamily transporters act as key factors in osmotic adjustment by balancing potassium homeostasis in cell growth and drought stress responses.     

Investigation of Critical Core Formulation and Process Parameters for Osmotic Pump Oral Drug Delivery

Push–pull osmotic pump (PPOP) tablets of a practically insoluble model drug were developed and the effect of various formulation and process parameters on tablet performance was evaluated in order to identify critical factors. The formulation factors such as the viscosity grade of polyethylene oxide as the primary polymer as well as the level and location of osmogen within the bilayer tablets led to a difference in performance of osmotic tablets and hence should be critically evaluated in the design of such dosage forms. Modification of granulation process, i.e., the granulating liquid composition or drying method of granules, did not impact the drug release from the osmotic tablets at the evaluated scale of this study. The influence of varying dose and aqueous solubility of other model drugs (i.e., theophylline, acetaminophen, and verapamil HCl) on the developed PPOP template was also investigated. Results showed that irrespective of the perceived complexity of development and manufacturing of osmotic pumps, the osmotic tablets in this study demonstrated a robust and yet flexible platform in accommodating different types of drug candidates, regardless of solubility, for the dose levels below 25% w/w of the pull layer formulation.     

Cellulose Acetate Butyrate: Ammonio Methacrylate Copolymer Blends as a Novel Coating in Osmotic Tablets

The objective of this work was the preparation of osmotic tablets using polymer blends of cellulose acetate butyrate (CAB) or ethylcellulose with ammonio methacrylate copolymer (Eudragit® RL). The advantage of these coatings in comparison to the traditionally used cellulose acetate is their solubility in safer organic solvents like ethanol. Polymer films were characterized with respect to their water uptake, dry mass loss, and mechanical properties. The effect of the polymer blend ratio on drug release and on the rupture force of the coating was investigated. In addition, the effect of drug solubility and content, pH and agitation rate of the release medium, and coating level and plasticizer content on the release were studied. With increased Eudragit® RL content in the coating blends, higher medium uptake of the film was observed, resulting in shorter lag times and faster drug release from the osmotic tablets. Replacing ethylcellulose with cellulose acetate butyrate as a coating material led to shorter lag times and faster drug release due to increased film permeability. In addition, CAB-based films had a higher strength and flexibility. The drug release was osmotically controlled and decreased with increasing coating level. It increased with increased drug solubility, plasticizer content, change of buffer species (acetate > phosphate), and decreased coating level. Agitation rate and drug content had no effect on the drug release. A 20% w/w coating level was sufficient for the tablet to tolerate forces of more than five times of the gastric destructive force reported in literature.     

Proniosomal Oral Tablets for Controlled Delivery and Enhanced Pharmacokinetic Properties of Acemetacin

Free-flowing proniosomal powders of acemetacin (AC) were prepared using the slurry method and maltodextrin as carrier. Positively charged proniosomes composed of 70:20:10 of Span 60/cholesterol (Chol)/stearylamine (SA), respectively, were successively compressed into tablets using direct compression method. The tablets were characterized for weight variability, friability, hardness, drug content uniformity, and dissolution properties. The in vivo evaluation of the prepared proniosomes (powder or tablet forms) after oral administration was investigated by the determination of AC and its active metabolite indomethacin (IND) in the blood of albino rabbits. Results indicated that the increase of Chol from 10% to 20% markedly reduced the efflux of the drug. Further Chol addition from 30% to 50% led to increased AC release rates. The proniosome tablets of AC showed greater hardness and disintegration time and less friability than AC plain tablets. The dissolution of proniosomal tablets indicated a lower drug release percentage compared to powdered proniosomes and AC plain tablets. The mean pharmacokinetic parameters of AC and IND from different formulations indicated increased t_1/2 and area under the curve (AUC) of both AC and IND for proniosomal tablets compared with both proniosomal powders and AC plain tablets. This study suggested the formulation of AC proniosomal powder into tablets to control and extend its pharmacologic effects.KEY WORDS: acemetacin, proniosomes, sustained-release tablet, pharmacokinetics     

Physicochemical Investigations and Stability Studies of Amorphous Gliclazide

Gliclazide (GLI), a poorly water-soluble antidiabetic, was transformed into a glassy state by melt quench technique in order to improve its physicochemical properties. Chemical stability of GLI during formation of glass was assessed by monitoring thin-layer chromatography, and an existence of amorphous form was confirmed by differential scanning calorimetry and X-ray powder diffractometry. The glass transition occurred at 67.5°C. The amorphous material thus generated was examined for its in vitro dissolution performance in phosphate buffer (pH 6.8). Surprisingly, amorphous GLI did not perform well and was unable to improve the dissolution characteristics compared to pure drug over entire period of dissolution studies. These unexpected results might be due to the formation of a cohesive supercooled liquid state and structural relaxation of amorphous form toward the supercooled liquid region which indicated functional inability of amorphous GLI from stability point of view. Hence, stabilization of amorphous GLI was attempted by elevation of T_g via formation of solid dispersion systems involving comprehensive antiplasticizing as well as surface adsorption mechanisms. The binary and ternary amorphous dispersions prepared with polyvinylpyrrolidone K30 (as antiplasticizer for elevation of T_g) and Aerosil 200® and/or Sylysia® 350 (as adsorbent) in the ratio of 1:1:1 (w/w) using kneading and spray-drying techniques demonstrated significant enhancement in rate and extent of dissolution of drug initially. During accelerated stability studies, ternary systems showed no significant reduction in drug dissolution performance over a period of 3 months indicating excellent stabilization of amorphous GLI.Key words: amorphous, gliclazide, solid dispersion, stability studies, T_g     

Effect of Drug Solubility on Polymer Hydration and Drug Dissolution from Polyethylene Oxide (PEO) Matrix Tablets

The purpose of the study was to investigate the effect of drug solubility on polymer hydration and drug dissolution from modified release matrix tablets of polyethylene oxide (PEO). Different PEO matrix tablets were prepared using acetaminophen (ACE) and ibuprofen (IBU) as study compounds and Polyox WSR301 (PEO) as primary hydrophilic matrix polymer. Tablet dissolution was tested using the USP Apparatus II, and the hydration of PEO polymer during dissolution was recorded using a texture analyzer. Drug dissolution from the preparations was dependent upon drug solubility, hydrogel formation and polymer proportion in the preparation. Delayed drug release was attributed to the formation of hydrogel layer on the surface of the tablet and the penetration of water into matrix core through drug dissolution and diffusion. A multiple linear regression model could be used to describe the relationship among drug dissolution, polymer ratio, hydrogel formation and drug solubility; the mathematical correlation was also proven to be valid and adaptable to a series of study compounds. The developed methodology would be beneficial to formulation scientists in dosage form design and optimization.     

吗啡皮下自控镇痛泵治疗难治性癌痛的前瞻性多中心随机对照研究

摘要 目的：观察吗啡皮下自控镇痛泵治疗难治性癌痛的临床疗效。方法：采用前瞻性多中心随机对照研究,应用治疗方法分为试验组和对照组,其中试验组使用皮下自控阵痛泵给药,对照组口服吗啡片剂,5 d为一疗程,共计观察3疗程。观察两组患者治疗后疼痛积分改善情况;每疗程吗啡日均用量;疼痛起效时间、最佳缓解时间;镇痛维持时间及剂量稳定天数、爆发痛情况;生活质量改善及不良反应发生率;疗程费用情况。结果：两组患者数字疼痛评分法(numerical rating scale,NRS)评分在治疗后均较镇痛前显著降低（P＜0.05）;在吗啡用量比较方面,试验组吗啡用量显著低于对照组同期用量;试验组在疼痛缓解时间、疼痛最佳缓解时间方面均显著优于对照组;治疗期间试验组平均镇痛维持时间明显长于对照组（P＜0.05）;两组患者治疗后体力状况分析标准(performance status,PS)评分较治疗前显著改善;试验组便秘、嗜睡不良反应发生率显著低于对照组（P＜0.05）。试验组每疗程费用明显低于对照组,具有明显经济优势。结论：吗啡皮下自控镇痛泵给药方式控制难治性癌痛临床疗效确切,止痛效果明显。与对照组比较,疼痛起效时间短,疗程较吗啡用量少,不良反应发生率低,改善了患者生活质量,且减轻了患者经济压力。     

An Intracellular Pathway Controlled by the N-terminus of the Pump Subunit Inhibits the Bacterial KdpFABC Ion Pump in High K+ Conditions

The heterotetrameric bacterial KdpFABC transmembrane protein complex is an ion channel-pump hybrid that consumes ATP to import K⁺ against its transmembrane chemical potential gradient in low external K⁺ environments. The KdpB ion-pump subunit of KdpFABC is a P-type ATPase, and catalyses ATP hydrolysis. Under high external K⁺ conditions, K⁺ can diffuse into the cells through passive ion channels. KdpFABC must therefore be inhibited in high K⁺ conditions to conserve cellular ATP. Inhibition is thought to occur via unusual phosphorylation of residue Ser162 of the TGES motif of the cytoplasmic A domain. It is proposed that phosphorylation most likely traps KdpB in an inactive E1-P like conformation, but the molecular mechanism of phosphorylation-mediated inhibition remains unknown. Here, we employ molecular dynamics (MD) simulations of the dephosphorylated and phosphorylated versions of KdpFABC to demonstrate that phosphorylated KdpB is trapped in a conformation where the ion-binding site is hydrated by an intracellular pathway between transmembrane helices M1 and M2 which opens in response to the rearrangement of cytoplasmic domains resulting from phosphorylation. Cytoplasmic access of water to the ion-binding site is accompanied by a remarkable loss of secondary structure of the KdpB N-terminus and disruption of a key salt bridge between Glu87 in the A domain and Arg212 in the P domain. Our results provide the molecular basis of a unique mechanism of regulation amongst P-type ATPases, and suggest that the N-terminus has a significant role to play in the conformational cycle and regulation of KdpFABC.     

Osmotic Adjustment and Osmotic Constituents in Roots of Mung Bean Seedlings

Osmotic adjustment in roots of mung bean seedlings (Vigna mungo(L.) Hepper) and the effect of cotyledon excision on the osmoticadjustment were investigated. The major osmotic constituentsin roots of intact seedlings were K⁺, Cl^–, free aminoacids and sugars (glucose, fructose and sucrose). All theseintracellular concentrations distinctly increased under osmoticstress and contributed to about 80% of the intracellular osmoticpressure of the root cell sap. Cotyledon excision remarkablysuppressed both the osmotic adjustment and the elongation inroots. However, the effect of cotyledon excision on intracellularK⁺ and Cl^– concentrations in roots was quite small. Twodifferent mechanisms are likely for the osmotic adjustment inroots. One is the K⁺ and Cl^–-dependent osmotic adjustmentwhich is cotyledon-independent, and the other is the osmoticadjustment dependent on the supply of free amino acids and sugarsfrom cotyledons. (Received September 20, 1986; Accepted January 14, 1987)     

Solubility of proteins

A theory is presented on the solubility of proteins, in the hydrated as well as in the dry state, and in water as well as in organic solvents. To this effect, colloidal stability is assimilated with the solubility of the proteins, considered as hydrated entities. By means of a surface thermodynamic approach it can be shown that an increase in size of a hydrated protein must lead to insolubility, even in the absence of any change in a protein's surface properties. This can be substantiated experimentally by comparing the surface properties of immune complexes with those of their constituent immunoglobulins, as well as by comparing some of the properties of intact tobacco mosaic virus with those of its monomeric capsid subunits. Insolubilization of proteins by means of charge interactions as well as by dehydration is studied; an explanation is given of why precipitation caused by charge interactions is more likely to lead to partial irreversible denaturation than precipitation caused by protein-protein interactions brought about by partial dehydration (e.g., by salting-out). A link is established between the smallness (or even the negative value) of the interfacial tension between given proteins and various solvents and their solubility in these solvents. The energy of hydration of proteins can also be measured, and the differences between the free energies of interaction of dried and hydrated proteins with water point toward the additional processes underlying the solubilization, i.e., toward the conformational change of a protein in the process of becoming hydrated. The parameter of conformational change of a protein, while becoming hydrated, appears to be more closely linked to its degree of hydration than to its hydration energy.     

Solubility of proteins

A theory is presented on the solubility of proteins, in the hydrated as well as in the dry state, and in water as well as in organic solvents. To this effect, colloidal stability is assimilated with the solubility of the proteins, considered as hydrated entities. By means of a surface thermodynamic approach it can be shown that an increase in size of a hydrated protein must lead to insolubility, even in the absence of any change in a protein's surface properties. This can be substantiated experimentally by comparing the surface properties of immune complexes with those of their constituent immunoglobulins, as well as by comparing some of the properties of intact tobacco mosaic virus with those of its monomeric capsid subunits. Insolubilization of proteins by means of charge interactions as well as by dehydration is studied; an explanation is given of why precipitation caused by charge interactions is more likely to lead to partial irreversible denaturation than precipitation caused by protein-protein interactions brought about by partial dehydration (e.g., by “salting-out”). A link is established between the smallness (or even the negative value) of the interfacial tension between given proteins and various solvents and their solubility in these solvents. The energy of hydration of proteins can also be measured, and the differences between the free energies of interaction of dried and hydrated proteins with water point toward the additional processes underlying the solubilization, i.e., toward the conformational change of a protein in the process of becoming hydrated. The parameter of conformational change of a protein, while becoming hydrated, appears to be more closely linked to its degree of hydration than to its hydration energy.     

Adaptive Growth Responses to Osmotic Stress of Hypocotyl Sections of Vigna unguiculata: Roles of the Xylem Proton Pump and IAA

The growth responses to osmotic stress of hypocotyl sectionsof Vigna unguiculata were studied by the xylem perfusion method.Hypocotyl sections shrank upon exposure to osmotic stress. Sectionsshowed no adaptive responses to osmotic stress when they werein an IAA-depleted condition as a result of perfusion with solutionsthat lacked IAA for 3–4 h. The correlation between thegrowth rate and the membrane potential of the xylem/symplastboundary (V^px) was very limited in the absence of IAA. By contrast,hypocotyl sections showed distinct adaptive responses to osmoticstress after perfusion with solutions that contained 10 µMIAA. In the presence of IAA, V^px increased in the negative directionand growth resumed in spite of the osmotic stress. The growthrate was closely correlated with the xylem membrane potential.Hyper-polarization of the membranes of the xylem/symplast boundaryalways preceded the recovery of growth under osmotic stress.It appears that IAA is essential for the adaptive recovery ofgrowth under osmotic stress and, moreover, that the xylem protonpump plays an indispensable role in modulating the growth ofhypocotyl sections. This result confirms prediction of an earliersimulation study using the apoplast canal model [Katou and Furumoto(1986) Protoplasma 133: 174, Katou and Enomoto (1991) PlantCell Physiol. 32: 343]. (Received June 27, 1996; Accepted October 28, 1996)