Comparison of a novel spray congealing procedure with emulsion-based methods for the micro-encapsulation of water-soluble drugs in low melting point triglycerides

The particle size characteristics and encapsulation efficiency of microparticles prepared using triglyceride materials and loaded with two model water-soluble drugs were evaluated. Two emulsification procedures based on o/w and w/o/w methodologies were compared to a novel spray congealing procedure. After extensive modification of both emulsification methods, encapsulation efficiencies of 13.04% tetracycline HCl and 11.27% lidocaine HCl were achievable in a Witepsol®-based microparticle. This compares to much improved encapsulation efficiencies close to 100% for the spray congealing method, which was shown to produce spherical particles of ～58 μm. Drug release studies from a Witepsol® formulation loaded with lidocaine HCl showed a temperature-dependent release mechanism, which displayed diffusion-controlled kinetics at temperatures ～25°C, but exhibited almost immediate release when triggered using temperatures close to that of skin. Therefore, such a system may find application in topical semi-solid formulations, where a temperature-induced burst release is preferred.     

Comparison of spray congealing and melt emulsification methods for the incorporation of the water-soluble salbutamol sulphate in lipid microparticles

Context: Salbutamol sulphate is widely used as bronchodilator for the treatment of asthma. Its use is limited by the relatively short duration of action and hence sustained delivery of salbutamol sulphate offers potential benefits to patients.

Objective: This study explores the preparation of lipid microparticles (LMs) as biocompatible carrier for the prolonged release of salbutamol sulphate.

Materials and methods: The LMs were produced using different lipidic materials and surfactants, by classical melt emulsification-based methods (oil-in-water and water-in-oil-in-water emulsions) and the spray congealing technique.

Results: For the LMs obtained by melt emulsification a lack of release modulation was observed. On the other hand, the sustained release of salbutamol sulphate was achieved with glyceryl behenate microparticles prepared by spray congealing. These LMs were characterized by scanning electron microscopy, X-ray diffractometry and differential scanning calorimetry. The drug loading was 4.72% (w/w). The particle size distribution measured by laser diffraction and electrical zone sensing was represented by a volume median diameter (Dv₅₀) of 51.7–71.4 µm. Increasing the atomization air pressure from 4 to 8 bar produced a decrease of the Dv₅₀ to 12.7–17.5 µm.

Conclusions: Incorporation of the hydrophilic salbutamol sulphate into LMs with sustained release characteristics was achieved by spray congealing.     

Characteristics of a novel phospholipid-based depot injectable technology for poorly water-soluble drugs.

Phospholipid concentrates in a water miscible solvent were explored as injectable formulations for the poorly water-soluble drugs, using the anti-infective PHA 244 as model substance. Formulations containing up to 70% w/v phospholipid could dissolve 15% PHA 244. The formulations showed excellent syringe-ability and no precipitation of the drug after dilution in an excess of water. The local tolerability and pharmacokinetics of the formulations were explored after subcutaneous injection into cattle. A slow release pattern over a 2-week period and excellent local tolerability at the injection site were observed. Considering the low manufacturing costs, related to the production of solutions, this SupraVail MLM (Membrane Lipid Matrix) technology is a cost-effective alternative to more expensive depot technologies for poorly water-soluble drugs with similar release characteristics, like sterile aqueous and oily drug substance suspensions, as cited in the literature.     

Clinical pharmacological equivalence of a novel FCH-free GTN spray with low ethanol content vs a FCH-containing GTN spray

The overall therapeutic equivalence of a fluorochlorohydrocarbon (FCH)-free glyceryl trinitrate (GTN) pump spray with a low ethanol content (TL) was investigated relative to an FCH-containing GTN spray (Nitrolingual; R), in terms of: (1) pharmacokinetic bioavailability, (2) pharmacodynamic responses as assessed by digital plethysmography (DPG), and (3) clinical perception upon application.Pharmacokinetically, the time courses of the plasma concentrations of GTN and its dinitrate metabolites, 1,2- and 1,3-GDN, subsequent to the sublingual administration of 0.8 mg GTN showed somewhat lower bioavailability of GTN and its metabolites than to the reference. Pharmacodynamically, the changes in the DPG signals after the application of 0.8 mg GTN with TL were biostatistically euivalent with R (estimated ratio TL/R for the maximum decrease of the ratio between the systolic a wave and c incisure: 0.98; 90% CI: 0.84–1.14; and for the average decrease of the c: a ratio: 0.97; 90% CI: 0.80–1.16). The time of occurrence of the maximum effect of TL was not significantly different from that of R (estimated difference TL-R: -2.25 min; 95% CI:-9.5 min to 2 min).In contrast, after the administration of an FCH-free GTN spray with a higher ethanol content (TH, active control), the effect had a slightly earlier onset (TH-R:-6 min, 95% CI: -9.5 to -2 min) and there was a higher average response (TH/R: 1.12: 90% CI: 0.95 to 1.34). However, TH was consistently judged to cause an extremely unpleasant burning sensation in the mouth and thus was perceived as distinctly different from R. In contrast, TL was well tolerated and could not be distinguished from R.Therefore only TL met the criteria of overall therapeutic equivalence to R.     

Development of a spray congealing process for the preparation of insulin-loaded lipid microparticles and characterization thereof.

A spray congealing process for the preparation of protein-loaded microparticles was developed. The influence of the process parameters atomization pressure and spraying temperature on particle size and process yield was investigated by experimental design. The employed spray congealing technique enabled the production of microparticles with yields ranging from 79% to 95% and median particle sizes (d(0.5)) from 182.2 to 315 microm. Insulin lipid microparticles could be prepared without any loss of insulin during the preparation process and the protein stability was not affected by the spray congealing process as investigated by HPLC-MS analysis. The stability of insulin encapsulated in lipid microparticles under release conditions over 28 days was assessed by investigating the residual insulin content. Starting after 3 days of release, a continuous increase of desamidoinsulin in the remaining particles of up to 7.5% after 28 days was observed. An additional degradation product was detected by HPLC and HPLC-MS analysis and identified as a covalent insulin dimer by MALDI-ToF. The microparticles did not show a burst release and testing the insulin lipid microparticles in a fibrin gel chondrocyte culture revealed that the released insulin was bioactive and had a significant effect on chondrocyte extracellular matrix production.     

《中国药典》药用辅料聚乙二醇凝点测定的探讨

目的：探究《中国药典》凝点检查法测定聚乙二醇系列药用辅料品种的适用性。 方法：比较了不同国家药典凝点测定方法的差异,筛选了多个方法参数并设置了不同的水平进行影响因素试验。 结果：实验结果显示,凝点读取方法、搅拌时间、冷却液温度、熔融温度和水分等因素均会影响聚乙二醇样品的凝点测定结果。 结论：按《中国药典》凝点检查法测定聚乙二醇样品凝点受到诸多实验因素的影响,其准确性和重复性仍需改进,当前凝点检查法在评价聚乙二醇样品纯度时的作用是有限的。     

生物技术药物中残留DNA检测方法的比较

生物技术药物是所有以生物质为原料的生物活性物质及其人工合成类似物通过现代生物技术制得的药物,包括细胞因子、重组蛋白、抗体、疫苗和寡核苷酸等,临床上已开始广泛应用,为制药工业带来了革命性变化.但是生物技术药物中残留DNA可能存在安全性问题,因此应尽可能将产品中残留DNA的水平降到最低.新版美国药典将推荐实时定量PCR法作为生物技术药物中宿主残留DNA检定的唯一标准方法.该法的技术优势在于序列特异性高、灵敏度高、重现性好,还可以实现定量检测,使得结果更为精确,从而为生物技术药物企业在工艺研究和成品质量控制方面提供了可靠的检测手段.此综述对4类检测方法进行了比较,重点比较两种实时定量方法.     

A novel method for encapsulation of poorly water-soluble drugs: precipitation in polyelectrolyte multilayer shells

A novel method to include poorly water-soluble substances into the polyelectrolyte capsules of defined size, stability, composition and affinity properties is proposed. Encapsulation explores the polarity gradient across the capsule wall. Capsules creation makes use of electrostatic interaction and can involve many substances as layer constituents, such as synthetic polyelectrolytes, proteins, nucleic acids, lipids and multivalent dyes. Using capsules made of synthetic polyelectrolytes as a model system was demonstrated how to prepare, to measure and to use this gradient for low molecular weigh materials encapsulation.     

A novel excipient, 1-perfluorohexyloctane shows limited utility for the oral delivery of poorly water-soluble drugs

The applicability of the semi-fluorinated alkane 1-perfluorohexyloctane (F6H8) as a novel excipient in lipid based drug delivery systems was studied. Solubility studies of 11 poorly water soluble drugs (cinnarizine, danazol, estradiol, fenofibrate, griseofulvin, halofantrine, lidocaine, prednisolone, probucol, rolipram and siramesine) showed significantly lower equilibrium solubility in F6H8 compared to soy bean oil (long chain triglyceride). F6H8 was miscible with medium chain triglycerides (MCT) but not miscible with long chain triglycerides, neither was pure F6H8 nor the mixture F6H8:MCT (1:1) miscible with 7 commonly used surfactants (Cremophor EL, Span 20, Span 80, Labrasol, Softigen 767 and Gelucire 44/14, polysorbate 80). In vitro lipolysis studies confirmed that F6H8 was non-digestible. F6H8:MCT (1:1) showed initially faster lipolysis compared to pure MCT. Thus, final phase lipolysis was lower indicating that F6H8 may affect the lipolysis of MCT. However, in vivo bioavailability studies in rats showed the same plasma concentration-time profiles when dosing 10 mg/kg halofantrine at two dose levels of F6H8, MCT or F6H8:MCT (1:1) (AUC ranged from 3058 to 3447 h ng/ml, T_max ～ 6.0 h, C_max ranged from 168 to 265 mg/ml). Generally, the addition of polysorbate 80 shortened the time to reach C_max (T_max ranged 1.3–4.5 h), but had limited effect on the bioavailability from F6H8 or MCT in combination with polysorbate 80 (4:1) (AUC ranged from 3807 to 4403 (h ng/ml)). Although a synergistic effect was obtained with halofantrine in F6H8:MCT:polysorbate 80 (2:2:1) (AUC 5574 ± 675 h ng/ml; mean ± SEM), it was not superior to dosing halofantrine in pure polysorbarte 80 (AUC 7370 ± 579 h ng/ml; mean ± SEM). The applicability of F6H8 as an excipient for future use in lipid based formulations for poorly water soluble drugs is therefore considered to be very limited.     

改善难溶性药物功效的一种新型给药系统——干酏剂的研究进展

干酏剂是一种将乙醇和药物同时包裹入水溶性聚合物壳内的固态微囊.乙醇的潜溶剂作用及喷雾干燥工艺可能产生的无定形药物,有利于包裹于干酏剂中的水难溶性药物快速分散并溶解于水性介质中,从而提高其溶出速率和生物利用度.本文综合近年来干酏剂研究的主要文献,从干酏剂的制剂成型工艺及机制、对难溶性药物体外溶出、体内吸收及生物利用度的影响,以及基于干酏剂的剂型设计及应用做一综述.     

A novel procedure for the analysis of drugs in whole blood by homogeneous enzyme immunoassay (EMIT)

This paper describes a procedure for the analysis of whole blood by six commonly used EMIT d.a.u. assays: barbiturates, benzodiazepines, cocaine metabolite, opiates, amphetamines, and the cannabinoid 20 assays using the Syva Autocarousel and the COBAS MIRA. The sensitivity of the method rivals that of other immunoassay methods, such as RIA, for the detection of drugs in blood. The procedure has been successfully applied to the analysis of several hundred postmortem forensic blood specimens.     

Solid dispersions,Part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

Introduction: The absorption of poorly water-soluble drugs, when presented in the crystalline state to the gastrointestinal tract, is typically dissolution rate-limited, and according to BCS these drugs belong mainly to class II. Both dissolution kinetics and solubility are particle size dependent. Nowadays, various techniques are available to the pharmaceutical industry for dissolution rate enhancement of such drugs. Among such techniques, nanosuspensions and drug formulation in solid dispersions are those with the highest interest.

Areas covered: This review discusses strategies undertaken over the last 10 years, which have been applied for the dissolution enhancement of poorly water-soluble drugs; such processes include melt mixing, electrospinning, microwave irradiation and the use of inorganic nanoparticles.

Expert opinion: Many problems in this field still need to be solved, mainly the use of toxic solvents, and for this reason the use of innovative new procedures and materials will increase over the coming years. Melt mixing remains extremely promising for the preparation of SDs and will probably become the most used method in the future for the preparation of solid drug dispersions.     

Solid dispersions, part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

INTRODUCTION: The absorption of poorly water-soluble drugs, when presented in the crystalline state to the gastrointestinal tract, is typically dissolution rate-limited, and according to BCS these drugs belong mainly to class II. Both dissolution kinetics and solubility are particle size dependent. Nowadays, various techniques are available to the pharmaceutical industry for dissolution rate enhancement of such drugs. Among such techniques, nanosuspensions and drug formulation in solid dispersions are those with the highest interest. AREAS COVERED: This review discusses strategies undertaken over the last 10 years, which have been applied for the dissolution enhancement of poorly water-soluble drugs; such processes include melt mixing, electrospinning, microwave irradiation and the use of inorganic nanoparticles. EXPERT OPINION: Many problems in this field still need to be solved, mainly the use of toxic solvents, and for this reason the use of innovative new procedures and materials will increase over the coming years. Melt mixing remains extremely promising for the preparation of SDs and will probably become the most used method in the future for the preparation of solid drug dispersions.     

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine

RATIONALE: Procedures for studying the effects of medications on satiation will assist the development of obesity medications. OBJECTIVES: Develop a procedure for measuring satiation during consumption of bland and highly palatable food and determine the effect of acute intramuscular administration of dexfenfluramine (DFEN), which increases serotonin levels, and memantine (MEM), which blocks N-methyl-D: -aspartate receptors. MATERIALS AND METHODS: A modified progressive ratio (PR) procedure was used to track changes in reinforcing strength when a food was consumed. The response requirement increased after each reinforcement, and reinforcing strength was estimated using the breakpoint (BP), which was the last completed response cost. There was one preferred food (sweet candy) and one chow pellet PR session per week. During each session, four male and four female adult baboons experienced three 1-h PR trials, separated by 30 min. Chow pellets were available at all other times. We examined the BP for one to 20 candies or chow pellets. Drug effects were examined when baboons had access to one and ten candies or chow pellets. RESULTS: BPs for candy were greater than for pellets. Varying the pellet/candy pieces per delivery produced an inverted U-shaped function on the first trial, i.e., maximal BP was observed for three items, and the BP for multiple items, but not a single item, decreased across trials, i.e., BP decreased with food intake and satiation. DFEN and MEM decreased responding with the greatest effects at ten deliveries, suggesting that DFEN and MEM enhanced satiation. CONCLUSION: Drugs that enhance satiation for several types of food may be particularly effective for decreasing food intake.     

应用纳米技术增加难溶性药物吸收的研究进展

随着高通量筛选等新技术的出现,涌现出许多难溶性的候选药物。利用纳米技术能减小难溶性药物的粒径,增加其溶解度、溶出度和口服生物利用度,减少食物效应的影响。本文介绍了纳米粒的制备方法,商用的专利纳米技术以及应用纳米技术成功上市的药品。纳米技术对改善生物药剂学分类体系（BCS）Ⅱ类药物的吸收具有广阔的前景。     

Percolation theory and the role of maize starch as a disintegrant for a low water-soluble drug

The objective of the present work is to investigate the presence or absence of a critical concentration of maize starch according to the percolation theory for a truly ternary system with respect to a minimum disintegration time. The results of this study show that the application of percolation theory is not limited to the study of binary systems. In this work it is shown how it can be used to analyze the behavior of binary and ternary systems for caffeine and mefenamic acid formulations containing a starch-based disintegrant. The percolation threshold p(c) can be described by the volumetric ratio of the disintegrant to the drug substance being equal to p(c) = 0.2 (v/v) in in which both components have similar average particle sizes. In addition, the behavior of the disintegration time in the neighborhood of the percolation threshold can be mathematically modeled with the basic equation of the percolation theory yielding a critical exponent q = 0.28 +/- 0.06.     

Beta-cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs

To evaluate the intestinal permeability of poorly water-soluble compounds, it is of importance to completely dissolve them in a medium and to avoid precipitation during experiments. This study was undertaken to find an agent possessing a high-solubilizing capacity and exhibiting minimal modulating impact on membrane integrity and absorption systems such as passive diffusion and carrier-mediated permeation. Phenytoin dissolution was compared in the presence of seven solubilizing agents at concentrations of 1, 2, or 5% using a centrifugation method. The capacity to dissolve phenytoin was great in β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin, followed by Tween 80. Those of methanol, dimethyl sulfoxide, dimethyl acetoamide, and polyethylene glycol 400 were much lower than expected. One percent β-CD did not alter the absorption of fluorescein isothiocyanate-dextran 4000 or the release of protein and lactate dehydrogenase into in situ loop contents, suggesting that 1% β-CD had no significant impact on the integrity of the intestinal membrane. One percent β-CD also did not alter the absorption of caffeine, ceftibuten, or rhodamine 123 from in situ jejunal loops, indicating no interference with passive diffusion and active transports mediated by a peptide transporter and P-glycoprotein. In conclusion, 1% β-CD is a suitable solubilizing agent for evaluating in situ intestinal absorption of poorly water-soluble compounds.     

Development of a novel method for predicting human volume of distribution at steady-state of basic drugs and comparative assessment with existing methods

The parameters characterizing tissue distribution refer to the tissue/plasma partition coefficients (Kp), which can be used to derive volume of distribution at steady-state (V_ss). The effort for predicting drug distribution in human has been further expanded to calculation methods using in vitro-based algorithms. The objective of the present study was to develop a novel prediction method to estimate human V_ss for moderate-to-strong bases. The predictive performance of the novel method was compared with other well established in vitro-based methods available in the literature. Relevant information collected from previous prediction studies of V_ss facilitated the development of the novel method. This was based on the calculation of V_ss from data on Kp, which were estimated by correlating the unbound tissue/plasma ratio in vivo (Kpu) with the unbound red blood cells partitioning (RBCu) determined in vitro. The comparative assessment of the novel correlation method with existing prediction methods of human V_ss was done using a literature dataset of 61 basic drugs (at least one pK_a ≥ 7). The five existing V_ss prediction methods published in the literature are comprised of four versions of tissue composition-based models along with the model of Lombardo using the principle of Oie-Tozer. The statistical analysis of the prediction performance indicated that the novel method demonstrated a greater degree of accuracy compared to all other published methods. The maximum percentage of predicted values that fall within a twofold-error range is 77% for the basic drugs tested. Overall, the present study describes the development and the assessment of the predictive performance of the novel prediction method of human V_ss based upon in vitro data, which appears to be superior based on the current dataset studied for basic drugs.