A new chromanone acid derivative from the nut oil resin of Calophyllum inophyllum.

One novel chromanone acid derivative, namely inocalophylline C (1), together with one known compound calophyllolide (2), were isolated from the methanolic extract of nut oil resin of Calophyllum inophyllum L., a medicinal plant widely distributed in Vietnam. The isolated compound structures were elucidated by spectroscopic methods and the absolute configuration of 1 was established by the single-crystal X-ray crystallography as ethyl (R) 3-((2 R,3R,6R)-4-hydroxy-2,3-dimethyl-6-((R)-5-methyl-2-(prop-1-en-2-yl)hex-4-en-1-yl)-6-(3-methylbut-2-en-1-yl)-5,7-dioxo-3,5,6,7-tetrahydro-2H-chromen-8-yl)-3-phenylpropanoate.

Influence of talc and hydrogenated castor oil on the dissolution behavior of metformin-loaded pellets with acrylic-based sustained release coating.

Multi-unit pellet system (MUPS) is of great interest as it is amenable to customization. MUPS comprises multi-particulates, usually as pellets or spheroids, which can be coated with diffusion barrier coatings. One commonly used diffusion barrier coating is the methacrylic acid copolymer, which can be used as a taste masking, enteric or sustained release polymer. While the versatility of methacrylic acid copolymers makes them pliable for pellet coating, there are impediments associated with their use. Additives commonly required with this polymer, including plasticizer and anti-adherent, have been shown to weaken the film strength. The objective of this study was to investigate the impact of osmotic pressure within the core on the sustained release coat integrity and functionality. Hydrogenated castor oil (HCO) was chosen as the additive to be studied. Metformin-loaded pellets, prepared via extrusion-spheronization, were coated with ethyl acrylate and methyl methacrylate copolymer (Eudragit RS 30 D) containing talc, talc-HCO, or HCO to different coat thicknesses. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. The swelling of the pellets when wetted was monitored by video imaging through a microscope. When coated to 7.5 % coat weight gain, coats with HCO slowed down drug release more than the other pellets. The pellets also swelled the most, which suggests that they were more resistant to the osmotic pressure exerted by metformin. For drugs which exert high osmotic pressure, HCO can serve as an efficient alternative to talc in the preparation of methacrylic acid copolymer coatings.

Understanding the release performance of pellets with hydrophobic inclusions in sustained-release coating.

The aim of this study was to evaluate how the addition of hydrophobic inclusions to sustained-release pellet film coat can affect drug release. Sustained-release formulations, in particular multiparticulate systems are gaining popularity because they are able to reduce the dosing frequency of drugs that require multiple dosing. In addition, the risk of dose dumping is low and local gastrointestinal irritation is minimised. Metformin-loaded pellets, prepared via extrusion-spheronisation, were coated with ethyl cellulose (EC)-based film coat, with and without hydrophobic inclusions to a series of coat thickness. Stearic acid 50 (SA) and hydrogenated castor oil (HCO) were the hydrophobic inclusions used. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. Release kinetics were analysed using the zero-order model. The physical properties of the pellets were characterised before and after dissolution. The addition of hydrophobic inclusions to EC-based film coat slowed down drug release, with SA slowing down drug release more than HCO. The influence of hydrophobic inclusions on drug release was clearly observable when the pellets were coated to 10% weight gain. It was postulated that the hydrophobic inclusions acted as physical barriers to increase the tortuosity of the diffusional path through the pellet film coat. The use of hydrophobic inclusions to control the rate of drug dissolution was shown to be promising. This could translate into potential cost and time savings with less materials and time used.

Equilibria, kinetics and mechanism for the degradation of the cytotoxic compound L-NG-nitroarginine.

L-NG-nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration. This work, for the first time, details a systematic study on the determination of equilibrium Ka constants and the rate law of LNNA degradation. The four Ka values of LNNA were determined to be 1.03, 1.10 × 10-2, 2.51 × 10-10, and 1.33 × 10-13 M. From the kinetic and equilibrium studies, we have shown that the deprotonated form of LNNA is the main form of LNNA that undergoes degradation in aqueous media at room temperature. The rate law of LNNA degradation was found to be first order with respect to OH- concentration and first order with respect to LNNA- concentration. The rate constant at 25 °C and 1 atm was determined to be 0.04453 M-1min-1. A base catalyzed mechanism of LNNA degradation was proposed based on the kinetic study. The mechanism was found to be very useful in explaining the discrepancies and changes of the rate law at different pH values. It is thus recommended that LNNA should be formulated as a concentrated solution in acidic conditions for maximum chemical stability during storage and be diluted with a basic solution to near physiological pH just before administration.

Evaluation of tablet punch configuration on mitigating capping by a quality by design approach.

Capping is a common problem in the manufacture of some types of tablets and unless resolved, the tableting process cannot proceed. Hence, all factors that can help to lessen the likelihood of capping without unnecessarily reduce turret speed and/or compaction force would be tenable. This study investigated the influence of tablet punch configuration on mitigation of tablet capping. Tablets were prepared from high-dose paracetamol-potato starch granules in a rotary tablet press with flat face plain (FFP), flat face bevel edge (FFBE) and flat face radius edge (FFRE) punch configurations. The directly compressible (DC) fillers tested were microcrystalline cellulose (MCC), pre-gelatinised starch (PGS) and lactose. Design of experiments (DoE), a tool of quality by design (QbD) paradigm, was used and the interaction of input variables (compression force, tablet punch configuration and DC filler) affecting the response factors (tablet hardness and capping rating) were evaluated. FFP punches were able to mitigate capping best. FFRE punches showed more potential than FFBE punches at alleviating capping in a particular compression force range, without the limitations of the FFP punches that produce cylindrical tablets that were more friable. Incorporation of PGS in the tablet formulation was observed to be more efficient at mitigating capping than the other DC fillers when FFBE and FFRE punches were used. Overall, this study serves as a model for prospective product development based on the QbD framework and the optimal use of compaction tools.

A study on the solid state characteristics of spray-congealed glyceryl dibehenate solid lipid microparticles containing ibuprofen.

OBJECTIVE: To study the solid state modifications of ibuprofen (IBU)-loaded spray-congealed glyceryl dibehenate (GB) solid lipid microparticles (SLMs) and the influence of polymeric additives using a combination of calorimetric and spectroscopic techniques. MATERIALS AND METHODS: IBU-loaded SLMs were produced by spray congealing with GB as the matrix material. Polyvinyl-2-pyrrolidone-vinyl-acetate (PVP/VA) and ethylcellulose (EC) were employed as additives. Of particular interest in this study were the solid state modifications of the drug and GB matrix induced by spray congealing and the effects of aging, as well as drug-matrix interactions. Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, hot stage microscopy and powder X-ray diffraction provided complementary analyses in understanding drug and lipid matrix polymorphism and interaction. The yield, morphology, drug content and encapsulation efficiencies of SLMs were also investigated. RESULTS AND DISCUSSION: Drug encapsulation efficiencies and yields of spray congealed SLMs were consistently high for all formulations. GB congealed as an unstable α-polymorph which reverted to the stable ß'-polymorph within a few weeks. PVP/VA accelerated the polymorphic conversion in less than a week, while EC took about a year. IBU formed a solid solution with GB regardless of the GB polymorphic form. CONCLUSIONS: Spray congealing is efficient for producing drug-loaded SLMs. It induces polymorphic changes in GB. The latter incorporated 20%, w/w IBU as a solid solution and polymeric additives exerted contrasting effects on the GB polymorphic conversion.

The chick chorioallantoic membrane imaging method as a platform to evaluate vasoactivity and assess irritancy of compounds.

OBJECTIVE: To determine if the chick chorioallantoic membrane (CAM) is a potential alternative that is capable of screening test substances for vasoactivity in terms of vessel diameter changes. The CAM was also evaluated as a tool for irritancy screening. METHODS: Visual assessment of the CAM for irritancy after the application of the test substance or solvent to its surface was made. An imaging based-in-vivo CAM model was developed by imaging CAM blood vessels in a pre-defined area using a semi-automatic image processing and analysis technique to measure blood vessel diameters. Solvents and drugs such as 70% v/v ethanol, normal saline, 5% w/v glucose monohydrate, glycerin, glucagon, N-methylpyrrolidone, nicotine, glyceryl trinitrate, glucagon, propranolol and caffeine were tested on the CAM. KEY FINDINGS: Propranolol, nicotine and glycerin were irritants on CAM. Changes in the diameters of fine blood vessels were accurately measured by high resolution image analysis. Vasoconstriction was seen with 70% v/v ethanol while vasodilation was displayed with glucagon and caffeine. The results reflected expected trends with evidence of feedback mechanisms ensuring homeostasis. CONCLUSION: The CAM model can be applied to assess pharmaceutical and cosmetic formulations in early development work to gain useful insights to potential irritancy and biological effects of components and formulations.

Antimicrobial and antioxidant activities of Cortex Magnoliae Officinalis and some other medicinal plants commonly used in South-East Asia.

BACKGROUND: Eight medicinal plants were tested for their antimicrobial and antioxidant activities. Different extraction methods were also tested for their effects on the bioactivities of the medicinal plants. METHODS: Eight plants, namely Herba Polygonis Hydropiperis (Laliaocao), Folium Murraya Koenigii (Jialiye), Rhizoma Arachis Hypogea (Huashenggen), Herba Houttuyniae (Yuxingcao), Epipremnum pinnatum (Pashulong), Rhizoma Typhonium Flagelliforme (Laoshuyu), Cortex Magnoliae Officinalis (Houpo) and Rhizoma Imperatae (Baimaogen) were investigated for their potential antimicrobial and antioxidant properties. RESULTS: Extracts of Cortex Magnoliae Officinalis had the strongest activities against M. Smegmatis, C. albicans, B. subtilis and S. aureus. Boiled extracts of Cortex Magnoliae Officinalis, Folium Murraya Koenigii, Herba Polygonis Hydropiperis and Herba Houttuyniae demonstrated greater antioxidant activities than other tested medicinal plants. CONCLUSION: Among the eight tested medicinal plants, Cortex Magnoliae Officinalis showed the highest antimicrobial and antioxidant activities. Different methods of extraction yield different spectra of bioactivities.

Process analytical technology: application to particle sizing in spray drying.

The purpose of this research was to explore the possibility of employing PAT for particle sizing during spray drying with the use of an in-line and at-line laser diffraction system. Microspheres were made using maltodextrin and modified starch as wall material and size results obtained using PAT compared with those determined with off-line laser diffraction and light microscopy. Median particle size results were highest for in-line laser diffraction, followed by at-line and off-line laser diffraction and finally light microscopy. This was due to the presence of agglomerates which were measured as discrete microspheres in the in-line set-up. At-line and off-line laser diffraction gave results more closely correlated with individual microsphere sizes due to agglomerate breakdown during the measurement process. Light microscopy allowed direct observation of the particle morphology, however, its use for particle sizing was tedious and sample size was much smaller compared to laser diffraction. Although PAT was found to be an efficient and convenient tool, careful data interpretation was needed taking into account the cohesiveness of the material measured. The at-line set-up appeared to be more suitable in this particular application.

A novel time-controlled release system based on drug-resin complexes and elementary osmotic pump.

A novel time-controlled system based on elementary osmotic pump tablet containing a drug-resin complexes (DRCs) core is presented. In the traditional osmotic pump tablets (OPTs), the lag time was always minimized. On the contrary, in the DRCs osmotic pump tablet (DRCOPT), the lag time was increased to achieve time-controlled delivery. The system led to a zero-order drug release after an initial lag time. Polyethylene oxide (PEO) N80 was used as suspension agent and NaCl was applied as ion-exchange, osmotic pressure (electrolyte supplementary) agent, respectively. To examine the mechanism of this system, drug release behaviors were investigated under conditions of various osmotic pressures. A new method of combination of conductivity and HPLC was applied to determine the different fractions of NaCl in producing osmotic pressure, ion-exchange and electrolyte supplement. The pharmacokinetic studies conducted in beagle dogs showed that a steadier and controlled drug release behavior was obtained compared with the traditional formulations. On the basis of prescription of the DRCOPT, a good in-vitro-in-vivo correlation (IVIVC, R(2)=0.9541) was achieved. In addition, a lag time of 4 h was observed in in vivo experiment, which indicated that the DRCOPT can be used in therapeutic regimens with the characteristics of chronotherapy.

Impact of a non-meltable additive on melt agglomeration with a hydrophobic meltable binder in high-shear mixer.

The present study aims to investigate the behavior of melt agglomeration with a low-viscosity hydrophobic meltable binder by using a non-meltable additive. The size, crushing strength, and pore size distribution of resultant agglomerates, the rheological, surface tension, and wetting properties of the molten binder, as well as, the flow characteristics of preagglomeration powder blend were determined. The use of additive showed contradictory agglomerate growth-promoting and -retarding effects on the molten binder surface tension and the interparticulate frictional forces. Critical concentration effects of additive corresponded to threshold transition of agglomeration-promoting to -retarding behavior were discussed.

Elucidation of spheroid formation with and without the extrusion step.

Spheroid formation mechanisms were investigated using extrusion-spheronization (ES) and rotary processing (RP). Using ES (cross-hatch), ES (teardrop), and RP (teardrop), spheroids with similar mass median diameter (MMD) and span were produced using equivalent formulation and spheronization conditions. During spheronization, the teardrop-studded rotating frictional surface, with increased peripheral tip speed and duration, produced spheroids of equivalent MMD and span to those produced by the cross-hatch rotating frictional plate surface. The roundness of these spheroids was also similar. RP required less water to produce spheroids of MMD similar to that of spheroids produced by ES. However, these RP spheroids were less spherical. Image analysis of 625 spheroids per batch indicated that the size distribution of RP spheroids had significantly greater SD, positive skewness, and kurtosis. Morphological examination of time-sampled spheroids produced by ES indicated that spheroid formation occurred predominantly by attrition and layering, while RP spheroids were formed by nucleation, agglomeration, layering, and coalescence. RP produced spheroids with higher crushing strength than that of ES-produced spheroids. The amount of moisture lost during spheronization for spheroids produced by ES had minimal influence on their eventual size. Differences in process and formulation parameters, in addition to size distribution and observed morphological changes, enabled a greater understanding of spheroid formation and methods to optimize spheroid production.

[Effects of interventional therapy with norcantharidin microsphere on hepatoma in rats and its mechanism].

OBJECTIVE: To investigate the effects of interventional therapy with norcantharidin-alginic acid/poly acid anhydride microspheres (N-MS) infusion via hepatic artery on hepatoma in rats. METHODS: N-MS was prepared by emulsion-chemical crosslink technique. Eighty-nine hepatoma-bearing rats were randomly divided into five groups, which were normal saline group, norcantharidin (NCTD) group, blank microsphere (B-MS) group, NCTD-lipiodol group and N-MS group. Normal saline, NCTD, B-MS, NCTD-lipiodol and N-MS were injected via hepatic artery accordingly. After the interventional therapy, eight rats from each group were observed for survival time, and the rest rats were killed on the 8th day after intervention to measure the tumor volume and necrostic degree. The apoptotic index of liver tumor cells was detected by TUNEL staining, and the expression of ki-67 was assayed by immuno-histochemical streptavidin-biotin peroxidase method. RESULTS: The survival time of the rats in the N-MS group was prolonged as compared with those in the other four groups, and the tumor volume of the rats in the N-MS group was smaller than those in the other four groups. The tumor growth rate and the expression level of ki-67 in the N-MS group were both significantly lower than those in the other four groups. The tumor necrotic degree and the apoptotic index in the N-MS group were significantly higher than those in the other four groups. CONCLUSION: Interventional therapy with N-MS could yield preferable therapeutic effects on hepatomas in rats. This anti-tumor efficacy may be associated with microvessel embolization in liver tumor and the sustained releasing of NCTD. Its inhibiting effect on tumor cell proliferation maybe result from decreasing the expression of Ki-67 and inducing the tumor cell apoptosis.

Herb-drug interactions: a literature review.

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Skin permeation of physostigmine from fatty acids-based formulations: evaluating the choice of solvent.

This study was conducted to gain an understanding of the enhancement mechanism of fatty acids in skin permeation of physostigmine (PHY) by using a series of fatty acids and two solvents of opposing lipophilicity (propylene glycol (PG) and mineral oil (MO)). Interaction between fatty acid and drug was proven using NMR and conductivity measurements that showed a dependence on type of solvent used. Permeation flux of physostigmine from mineral oil-based formulations to skin was increased as solubility of physostigmine in mineral oil was enhanced in the presence of fatty acids having a longer chain. Thus, the dominant role of fatty acids in mineral oil was to increase solubility of physostigmine in the formulations that increased the driving force for physostigmine permeation through skin. As for propylene glycol, enhancement caused by fatty acids was attributed to their ability to increase the lipophilicity of formulation and to disrupt the lipid bilayers within the stratum corneum (SC). In conclusion, fatty acids enhancement for drug permeation across the skin was found to be dependent on the solvent used. Among various formulations here, oleic acid in mineral oil yielded fast permeation of PHY with a short lag time, which may be a good vehicle for transdermal delivery of PHY.

Investigation of melt agglomeration process with a hydrophobic binder in combination with sucrose stearate.

The melt agglomeration process of lactose powder with hydrogenated cottonseed oil (HCO) as the hydrophobic meltable binder was investigated by studying the physicochemical properties of molten HCO modified by sucrose stearates S170, S770 and S1570. The size, size distribution, micromeritic and adhesion properties of agglomerates as well as surface tension, contact angle, viscosity and specific volume of molten HCO, with and without sucrose stearates, were examined. The viscosity, specific volume and surface tension of molten HCO were found to be modified to varying extents by sucrose stearates which are available in different HLB values and melt properties. The growth of melt agglomerates was promoted predominantly by an increase in viscosity, an increase in specific volume or a decrease in surface tension of the molten binding liquid. The agglomerate growth propensity was higher with an increase in inter-particulate binding strength, agglomerate surface wetness and extent of agglomerate consolidation which enhanced the liquid migration from agglomerate core to periphery leading to an increased surface plasticity for coalescence. The inclusion of high concentrations of completely meltable sucrose stearate S170 greatly induced the growth of agglomerates through increased specific volume and viscosity of the molten binding liquid. On the other hand, the inclusion of incompletely meltable sucrose stearates S770 and S1570 promoted the agglomeration mainly via the reduction in surface tension of the molten binding liquid with declining agglomerate growth propensity at high sucrose stearate concentrations. In addition to being an agglomeration modifier, sucrose stearate demonstrated anti-adherent property in melt agglomeration process. The properties of molten HCO and melt agglomerates were dependent on the type and concentration of sucrose stearate added.