Use of FT-NIR transmission spectroscopy for the quantitative analysis of an active ingredient in a translucent pharmaceutical topical gel formulation

The objective of this study was to demonstrate the use of transmission Fourier transform near-infrared (FT-NIR) spectroscopy for quantitative analysis of an active ingredient in a translucent gel formulation. Gels were prepared using Carbopol 980 with 0%, 1%, 2%, 4%, 6%, and 8% ketoprofen and analyzed with an FT-NIR spectrophotometer operated in the transmission mode. The correlation coefficient of the calibration was 0.9996, and the root mean squared error of calibration was 0.0775%. The percent relative standard deviation for multiple measurements was 0.10%. The results prove that FT-NIR can be a good alternative to other, more time-consuming means of analysis for these types of formulations.     

Design and production of gentamicin/dextrans microparticles by supercritical assisted atomisation for the treatment of wound bacterial infections

In this work, the supercritical assisted atomisation (SAA) is proposed, for the first time, for the production of topical carrier microsystems based on alginate–pectin blend. Gentamicin sulphate (GS) was loaded as high soluble and hygroscopic antibiotic model with poor flowability. Particularly, different water solutions of GS/alginate/pectin were processed by SAA to produce spherical microparticles (GAP) of narrow size (about 2 μm). GS loading was varied between 20% and 33% (w/w) with an encapsulation efficiency reaching about 100%. The micronised powders also showed high flow properties, good stability and constant water content after 90 days in accelerated storage conditions. The release profiles of the encapsulated drug were monitored using vertical diffusion Franz cells to evaluate the application of GAP microsystems as self-consistent powder formulation or in specific fibres or gels for wound dressing. All formulations showed an initial burst effect in the first 6 h of application (40–65% of GS loaded), and in particular GAP4 produced with a GS/alginate/pectin ratio of 1:3:1, exhibited the ability to release GS continuously over 6 days. Antimicrobial tests against Staphylococcus aureus indicated that GS antibiotic activity was preserved at 6 days and higher than pure GS at 12 and 24 days for all SAA formulations, especially for GAP1.     

GC—MS法对中药复方酸枣仁汤及其主要单味药超临界流体萃取物的成分分析

目的:研究中药复方酸枣仁汤及其主要单味药超临界流体萃取物化学成分的差异。方法:采用超临界流体萃取技术和传统水蒸气蒸馏法制备供试品溶液,运用 GC-MS 法对复方及其主要单味药的超临界流体萃取物和水蒸气蒸馏物进行化学成分分析。结果:共鉴定出37个化合物,其中2,4-癸二烯醛、棕榈酸甲酯、棕榈酸乙酯为首次从酸枣仁油中发现;4-甲基-3-环戊烯-1醇、安息油、4-羟基-3-甲氧基安息香醛、1,2,3,4-四氢萘烯、4-甲基苯酚、3-甲基-7-甲氧基苯并吡喃、4-甲氧基苊烯、4,5-二甲氧基苯环丁烯醇8个化合物为首次从川芎油中发现。结论:复方酸枣仁汤与其主要单味药超临界流体萃取物的化学成分存在一定差异,研究结果为探讨复方共提和单味药分提的化学成分变化规律提供了一定的依据。     

Carbon dioxide supercritical fluid extracts from yarrow and rose hip herbal dust as valuable source of aromatic and lipophilic compounds

The present study was designed to demonstrate the potential of supercritical extracts from Achillea millefolium and Rosa canina herbal dust, and their mixtures, as a source of valuable aromatic and lipophilic compounds. The supercritical carbon dioxide extraction (SFE-CO₂) was performed at the pressures from 10-30 MPa, providing the total extraction yields (EY) in the range from 0.12 to 10.57%, being the highest when pure R. canina herbal dust was extracted using SFE-CO₂ at 30 MPa for 5 h. Chemical profiles of SFE-CO₂ extracts were determined by GC-MS and GC-FID. Oxygenated monoterpenes and sesquiterpene hydrocarbons were among the most abundant compounds in the extracts produced from A. millefolium and mixtures with a higher share of A. millefolium herbal dust. In the same mixtures, at the pressure of 10 MPa, a cosolvent effect was observed, which provided enhanced extraction of eucalyptol. The major tocol in A. millefolium and R. canina mixtures was α-tocopherol (589.49 mg/L). By investigating the influence of extraction pressure, it has been determined that higher compound recoveries could be obtained at lower pressures. The results clearly demonstrate that SFE-CO₂ extracts of the A. millefolium and R. canina and their herbal dust mixtures are a promising source of valuable compounds to be used in pharmaceutical formulations.     

超临界CO_2萃取与水蒸气蒸馏法提取太子参挥发油化学成分气质联用研究

目的:分析比较采用超临界CO2流体萃取法与水蒸气蒸馏法提取的太子参提取物中挥发性化学成分的异同。方法:使用水蒸馏提取法和超临界CO2萃取技术从太子参中提取挥发性成分,用归一化法测定其百分含量。用气相色谱-质谱(GC-MS)计算机联用技术分离鉴定其中的化学组成。结果:太子参超临界CO2流体萃取物中初步鉴定了33种成分,主要成分为:亚油酸乙酯(28.70%)、n-十六酸(23.12%)、3-糠醇(5.51%)等;水蒸气蒸馏法提取挥发油初步鉴定了17种成分,主要成分为2-丙基呋喃(22.45%)、3-糠醇(19.78%)、3-乙基-3-甲基戊烷(19.47%)。结论:2种方法提取的挥发油化学成分差异较大,超临界CO2流体萃取法提取的挥发油能更真实、全面地反映太子参药材中的化学成分。     

Potential applications and human biosafety of nanomaterials used in nanomedicine

With the rapid development of nanotechnology, potential applications of nanomaterials in medicine have been widely researched in recent years. Nanomaterials themselves can be used as image agents or therapeutic drugs, and for drug and gene delivery, biological devices, nanoelectronic biosensors or molecular nanotechnology. As the composition, morphology, chemical properties, implant sites as well as potential applications become more and more complex, human biosafety of nanomaterials for clinical use has become a major concern. If nanoparticles accumulate in the human body or interact with the body molecules or chemical components, health risks may also occur. Accordingly, the unique chemical and physical properties, potential applications in medical fields, as well as human biosafety in clinical trials are reviewed in this study. Finally, this article tries to give some suggestions for future work in nanomedicine research. Copyright © 2017 John Wiley & Sons, Ltd.     

Evaluation of oleoresin capsicum of Capsicum frutescenes var. Nagahari containing various percentages of capsaicinoids following inhalation as an active ingredient for tear gas munitions

Comparative efficacy as peripheral sensory irritant, oral and inhalation exposure studies were carried out on oleoresin capsicum (OC) of Capsicum frutescence var. Nagahari containing various percentages of capsaicinoids and two synthetic isomers of capsaicin in Swiss albino male mouse model to come up with a suitable active ingredient from natural source for tear gas munitions. The compounds screened were OC having varying percentages of capsaicinoids (20, 40 and 80%, respectively) and synthetic isomers (E and Z) of capsaicin (8-methyl-N-vanillyl-6-nonenamide). Mice were exposed to pyrotechnically generated smoke of the compounds in an all glass static exposure chamber for 15?min to determine acute inhalation toxicity (LC₅₀) and quantitative sensory irritation potential (RD₅₀). Acute oral median lethal dose (LD₅₀) was also evaluated. Safety index of tear gas (SITG), a ratio of lethal concentration 50% (LC₅₀) and the concentration which depresses respiration by 50% (RD₅₀) due to peripheral sensory irritation is also proposed. The compound having highest SITG is considered as the most suitable to be used for tear gas munitions. The study revealed that oleoresin capsicum containing 40% capsaicinoids had the highest SITG among the compounds studied. The oral dosage versus mortality pattern of some compoundsdid not follow a true dose–response curve (DRC); however, following inhalation, all the compounds followed DRC. It was concluded that oleoresin capsicum (40% capsaicinoids) may be considered as the most suitable and environmental friendly compound from natural source to be used as an active ingredient for tear gas munitions.     

Development of HPLC analytical protocols for quantification of artemisinin in biomass and extracts

Quantification of artemisinin purity and amount in plant material and extracts to date has been characterized by a considerable inconsistency in values. This is likely to be due to the adoption of varied analytical procedures and use of inappropriate to the specific applications analytical techniques. In this paper we are attempting to further develop artemisinin analysis to the point where a universally acceptable reference method is available to the research and end-users communities. Thus, we have developed and validated an HPLC-RI method and optimized an HPLC-ELSD method. We used the gradient HPLC-UV method recommended by the current artemisinin monograph as a comparison for the method improvements presented herein, and show the limitations for its application scope. The data reported should help to allow more reliable laboratory analysis of artemisinin in both pure samples and in Artemisia annua extracts.     

Development,validation and transfer of a Near Infrared method to determine in-line the end point of a fluidised drying process for commercial production batches of an approved oral solid dose pharmaceutical product

Pharmaceutical companies are progressively adopting and introducing the principles of Quality by Design with the main purpose of assurance and built-in quality throughout the whole manufacturing process. Within this framework, a Partial Least Square (PLS) model, based on Near Infrared (NIR) spectra and humidity determinations, was built in order to determine in-line the drying end point of a fluidised bed process. The in-process method was successfully validated following the principles described within The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use – ICH Q2 (r1) – Validation of Analytical Procedures: Text and Methodology. However, in some aspects, the cited guidelines were not appropriate to in-process methods developed and validated exclusively with in-line samples and implemented in dynamic systems, such as drying processes. In this work, a customized interpretation of guidelines has been adopted which provided the framework of evidence to support a validated application.     

Poly(2-Ethyl-2-Oxazoline) as an Alternative to Poly(Vinylpyrrolidone) in Solid Dispersions for Solubility and Dissolution Rate Enhancement of Drugs

Poly(2-ethyl-2-oxazoline) (PEOX), a biocompatible polymer considered as pseudopolypeptide, was introduced as a potential alternative to the commonly used polymer, poly(vinylpyrrolidone) (PVP) for the preparation of solid dispersion with a poorly soluble drug. Glipizide (GPZ), a Biopharmaceutical Classification System class II model drug, was selected for solubility and dissolution rate study. GPZ-polymer solid dispersions and physical mixtures were characterized and investigated by X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, and FTIR spectroscopy. The impact of polymers on crystal nucleation kinetics was studied, and PEOX exhibited strong inhibitory effect compared with PVP. Solubility and dissolution behavior of the prepared solid dispersions and their physical blends were in vitro examined and evaluated. A significant enhancement in GPZ solubility was obtained with PEOX compared with the pure drug and solid dispersion with PVP. A big improvement in the intrinsic dissolution rate (45 times) and dissolved amount of GPZ (58 times) was achieved with PEOX in fasted state simulated intestinal fluid, against comparable enhancement observed with PEOX and PVP in phosphate buffer at pH 6.8. Lower molecular weight of PEOX-5K (5000 g/mol) was found to be superior to higher molecular weight PEOX-50K (50,000 g/mol) in the improvement of dissolution behavior. The findings of this study with GPZ as a model drug introduce lower molecular weight PEOX as a promising polymeric carrier toward better oral bioavailability of poorly soluble drugs.     

Liposomes and influenza viruses as an in vitro model for membrane interactions II. Influence of vesicle size and preparation methods

As previously demonstrated, membrane fusion and transfer of prodrug-type molecules between membranes can be studied with the octadecylrhodamine B chloride (R18) marker. We use this assay with PR8 influenza viruses and small (SUV) or large (LUV) unilamellar liposomes containing the virus receptor G_D1a as interacting partners in order to analyse the effect of membrane curvature on fusion and transfer. Computer analysis revelaed no difference in the kinetics of fusion between PR8 with large or small liposomes respectively. Lipid transfer, however, is about 5 to 6 times faster from SUV than from LUV. We also tested the influence of the production method for liposomes, namely detergent dialysis, sonication and extrusion on membrane interactions. Fusion is not affected by either, whereas transfer is slower with liposomes produced by sonication.     

Design,synthesis and iodination of an Arg‐Arg‐Leu peptide for potential use as an imaging agent for human prostate carcinoma

The aim of this work was to design and synthesize a radioiodinated peptide containing arginine–arginine–leucine (RRL) functionality as a potential imaging agent of tumor angiogenesis. The RRL peptide was synthesized using the Fmoc solid phase method and identified by MS analysis after purification by HPLC. The RRL peptide was labeled with ¹³¹I by the Chloramine‐T method and purified through Sephadex G‐25 column. Furthermore, the ¹³¹I labeled peptide was used to evaluate its biodistribution. SPECT imaging was carried out at 24 h after the ¹³¹I labeled RRL peptide was injected into BALB/c nude mice bearing human prostate carcinoma. For the first time we have shown that a radiolabelled RRL peptide appears to be useful as a tumor angiogenic endothelium imaging agent for the diagnosis of the human prostate carcinoma. Copyright © 2008 John Wiley & Sons, Ltd.     

Novel design and synthesis of a radioiodinated glycolipid analog as an acceptor substrate for N‐acetylglucosaminyltransferase V

Guided by the known molecular recognition interactions between N‐acetylglucosaminyltransferase V (GnT‐V) and certain synthetic substrates, we synthesized a radiolabeled double‐stranded glycolipid composed of a long‐chain alkyl unit and a radioiodinated phenylalkyl unit, [¹²⁵I]‐2‐[N‐(2‐hydroxy‐3‐hexadecyloxy)propyl‐15‐(4‐iodophenyl)pentadecanecarboxamido]ethyl 2‐acetamido‐2‐deoxy‐β‐d ‐glucopyranosyl‐(1→2)‐α‐d ‐mannopyranosyl‐(1→6)‐β‐d ‐glucopyranoside ([¹²⁵I]2), as a novel intravital glycolipid mimic substrate of GnT‐V. The radioactive iodine (¹²⁵I) was incorporated via iododestannylation of the phenyltributyltin derivative, 2‐[N‐(2‐acetoxy‐3‐hexadecyloxy)propyl‐15‐(4‐tributylstannylphenyl)pentadecanecarboxamido]ethyl 3,4,6‐tri‐O‐acetyl‐2‐acetamido‐2‐deoxy‐β‐d ‐glucopyranosyl‐(1→2)‐3,4,6‐O‐acetyl‐α‐d ‐mannopyranosyl‐(1→6)‐2,3,4‐tri‐O‐acetyl‐β‐d ‐glucopyranoside (26). Subsequent deacetylation at the final step afforded [¹²⁵I]2.     

Synthesis and characterization of 99mTc‐labelled biologically active molecules using borohydride exchange resin as a reducing agent for the preparation of radiopharmaceuticals

A novel and efficient method for preparing ^99mTc‐complexes of radiopharmaceuticals has been developed by reacting [^99mTc]pertechnetate with a ligand in the presence of borohydride exchange resin (BER) as a reducing agent. The latter is stable over a wide range of pH (2–11) and thus can be used with biologically active compounds without the formation of insoluble ^99mTcO₂ or SnO₂ colloids. Since the radiolabelled complexes are produced with high radiochemical purity and labelling efficiency under milder conditions than those required for the conventional reducing agents, the latter can be replaced. The method is expected to be applicable to the preparation of ^99mTc‐radiopharmaceuticals. Copyright © 2004 John Wiley & Sons, Ltd.     

Behavioral and physiological effects associated with changes in muscarinic receptors following administration of an irreversible cholinergic agonist (BM 123)

Previous work in our laboratory has shown that the aziridinium ion of BM 123 (N-[4(2-chloroethylmethylamino)-2-butynyl]-2 pyrrolidone) is a potent and selective muscarinic agonist and binds irreversibly to muscarinic receptors (mAChR). The present series of experiments was designed to study the effects of BM 123 on behavioral and physiological variables known to be sensitive to manipulations of the cholinergic neurotransmitter system. BM 123 was injected into the tail vein of Sprague-Dawley rats, reducing mAChR to approximately 10% of normal as judged by [³H](–)QNB binding. Oxotremorine was injected IV for purposes of comparison. Behavioral and physiological variables were measured daily for 26 days. Physiological variables (e.g., tremor, chromodacryorrhea, salivation, and temperature) showed effects in less than 5 min after injection and returned to their pretreatment baselines within minutes. Nociceptive thresholds, dependent on sensory-perceptual processes, showed peak changes of approximately +230% and returned to normal within hours. Motoric responses, i.e., drinking and general activity, recovered in 3–4 days. Learned responses and those requiring temporal discrimination took 8–11 days to recover and were the only responses paralleling the return of the mAChRs to their normal levels. Changes elicited by oxotremorine recovered more rapidly than those elicited by BM 123. The results suggest that the different variables measured are dependent on different densities of functional receptors. Implications for a theoretical model are discussed.     

Duocarmycin-based antibody–drug conjugates as an emerging biotherapeutic entity for targeted cancer therapy: Pharmaceutical strategy and clinical progress

Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody–drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status. Nevertheless, progress in duocarmycin-based ADCs also faces challenges, with setbacks including the termination of BMS-936561/MDX-1203. In this review, we discuss issues associated with the efficacy, pharmacokinetic profile, and toxicological activity of these biotherapeutics. Furthermore, we summarize the latest advances in duocarmycin-based ADCs that have different target specificities and linker chemistries. Evidence from preclinical and clinical studies has indicated that duocarmycin-based ADCs are promising biotherapeutics for oncological application in the future.