Paul Wan Sia Heng

Herb-drug interactions: a literature review.

AbstractHerbs 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.

Drug encapsulation in alginate microspheres by emulsification

A method based on an emulsification process was developed for the production of calcium alginate microspheres. Isopropyl alcohol and acetone, which are strong dehydrating agents, were used to aid in the hardening and drying of the microspheres. However, the amount of drug encapsulated was very low. This was due to the drug being soluble in the dehydrating solvents. In the absence of the solvents a high percentage of drug was encapsulated, and this was further increased by forming the microspheres by phase inversion. It was also found that a suspension of the drug particles was required for effective microencapsulation. The efficiency of drug encapsulation generally increased with the ratio of drug to encapsulating material. The microspheres produced were free-flowing and most of them were smaller than 150 microns.

Design of controlled-release solid dosage forms of alginate and chitosan using microwave.

The influence of microwave irradiation on the drug release properties of alginate, alginate-chitosan and chitosan beads was investigated. The beads were prepared with the highest possible concentration of polymer by an extrusion method. Sulphathiazole was selected as a model drug. The beads were subjected to microwave irradiation at various combinations of irradiation power and time. The profiles of drug dissolution, drug content, drug stability, drug polymorphism, drug-polymer interaction, polymer crosslinkage and complexation were determined by dissolution testing, drug content assay, differential scanning calorimetry (DSC) and fourier transform infra-red spectroscopy (FTIR). The chemical stability of the drug entrapped in the beads was unaffected by the microwave irradiation. However, the drug in the chitosan beads underwent polymorphic changes. Polymorphic changes were prevented by means of drug-alginate interaction in alginate and alginate-chitosan beads. Changes in the polymorphic state of drug were found to have insignificant effect on the drug release profiles of chitosan beads. The release-retarding property of alginate and alginate-chitosan beads was significantly enhanced by subjecting the beads to microwave irradiation. Positively charged calcium ions and chitosan are known to interact with negatively charged alginate. DSC and FTIR analyses indicated that the reduction in rate and extent of drug released from the treated beads was primarily due to additional formation of non-ionic bonds, involving alginate crosslinkage and alginate-chitosan complexation. The results showed that microwave technology can be employed in the design of solid dosage forms for controlled-release application without the use of noxious chemical agents.

Investigation of the influence of mean HPMC particle size and number of polymer particles on the release of aspirin from swellable hydrophilic matrix tablets

The effects of hydroxypropyl methylcellulose (HPMC) of different particle size ranges, size distributions and concentrations on the release behaviour of aspirin from a swellable matrix tablet system were studied. A mean HPMC (Methocel K15M Premium) particle size of 113 microm was identified as a critical threshold in this study. Drug release rate increased markedly when polymer particle size was increased above 113 microm. Release rate was much less sensitive to changes in particle size below 113 microm. Aspirin release mechanism followed first order kinetics where mean HPMC particle size was below 113 microm. Release mechanism deviated from first order kinetics when the mean particle size was above 113 microm. Polymer fractions with similar mean particle size but differing size distribution were also observed to influence drug release rate but not release mechanism. First order release constant K(1) was found to be quantitatively related to the reciprocal of the cube root of both mean polymer particle size and number of polymer particles in the matrix.

Production of alginate microspheres by internal gelation using an emulsification method

Alginate is a natural polysaccharide found in brown algae. Alginates are widely used in the food and pharmaceutical industries and have been employed as a matrix for the entrapment of drugs, macromolecules and biological cells. Alginate microspheres can be produced by the external or internal gelation method using calcium salts. The addition of calcium chloride solution in the final phase of production of microspheres by external gelation method using an emulsification technique causes the disruption of the equilibrium of the system being stirred, resulting in a significant degree of clumping of microspheres. Therefore, in this study, production of alginate microspheres by the internal gelation method using a modified emulsification technique was explored. The influence of calcium salt, added in varying amounts and at different stages, on the morphology of the microspheres was investigated. The effects of other hardening agents and different drying methods were also studied.

Cross-linking mechanisms of calcium and zinc in production of alginate microspheres

Calcium chloride and zinc sulphate were used to cross-link alginate microspheres prepared by an emulsification method. The microspheres cross-linked by a combination of these two salts showed different morphology and slower drug release compared with those cross-linked by the calcium salt alone. From viscosity study, it was found that zinc cations interacted with the alginate molecules to a greater extent than calcium cations. The varying effects of the salts on the properties of the microspheres were largely attributed to their ability to interact with the alginate molecules.

Effect of oil loading on microspheres produced by spray drying

Oil-loaded microspheres were produced by spray drying emulsions consisting of fish oil and modified starch suspensions with different oil loadings. The emulsion stability was assessed by oil droplet size analysis. Microspheres were characterized in terms of size, morphology, yield and microencapsulation efficiency. It was found that an increase in oil loading resulted in emulsions containing larger oil droplets. This corresponded with larger mean microsphere diameters and rounder microspheres. However, high oil loadings produced lower yields and affected microencapsulation efficiencies.

Relationship Between Swelling and Drug Release in a Hydrophilic Matrix

AbstractHydroxypropylmethylcellulose (HPMC) is widely used for controlled-release preparations. The process of drug release is controlled by matrix swelling and polymer dissolution. This study examines the mechanism of behaviour of HPMC in a polymer-drug directly-compressed matrix. The results obtained show that the swelling of HPMC which can be described by first-order kinetics is affected by concentration and viscosity grade of the polymer. This swelling action of HPMC in turn is controlled by the rate of water uptake into the matrices. An inverse relationship exists between the drug release rate and matrix swelling rate. This implies that HPMC swelling is one of the factors affecting drug release. The swelling behaviour of HPMC is therefore useful in predicting drug release.

Spheronization conditions on spheroid shape and size

Abstract The effects of Spheronization speed and residence time on the size and sphericity of microcrystalline cellulose (MCC)-lactose spheroids were investigated. Generally, spheroids became larger and more spherical with an increase in the residence time and Spheronization speed. With very high speeds or long residence times, small spheroids resulted. It was found that a combination of speeds ranging from 1000 to 2000 rpm and residence times between 5 and 15 min may be used to produce spheroids with a modal fraction in a size range of 0.7–1.0 mm. The effects of varying MCC content and amount of water required for Spheronization were also studied. The addition of a larger amount of water produced spheroids with larger mass median diameters. A higher proportion of MCC required correspondingly a greater amount of water to form spheroids of a certain mean size. An equation could be used to predict the quantity of water needed to produce spheroids of a required size range. Variation in the particle size of the lactose used also affected the size of spheroids formed. The coarser lactose grade produced larger spheroids. Granule size distribution and sphericity were found to be dependent on the operating conditions. Therefore, with a particular formulation, the variable parameters must be suitably adjusted to complement each other for successful Spheronization.

Improved formulation of photosensitizer chlorin e6 polyvinylpyrrolidone for fluorescence diagnostic imaging and photodynamic therapy of human cancer

An improved formulation of the photosensitizer chlorin e6 (Ce6) in combination with the hydrophilic polymer polyvinylpyrrolidone (PVP) was investigated for its potential clinical applications in fluorescence diagnosis and photodynamic therapy (PDT) of cancer. This study reports the comparative preclinical biodistribution and efficacy of Ce6 delivered with or without PVP versus dimethyl sulfoxide (DMSO). The safety and fluorescence pharmacokinetics of Ce6-PVP in humans was also accessed. Biodistribution results showed that Ce6-PVP had higher tumor to normal tissue ratio compared to the other formulations. The sensitivity and specificity derived from the area under the receiver operating characteristics curves showed that the formulations were able to discriminate tumor from peritumoral muscle in the following order: Ce6-PVP > Ce6 > Ce6-DMSO. In vitro PDT results showed that Ce6-PVP was found to induce selective phototoxicity in leukemic cells compared to peripheral mononuclear blood cells. In addition, in vivo light irradiation at 1h after Ce6-PVP was found to induce greater tumor necrosis without causing animal toxicity. In patients, preferential accumulation of Ce6-PVP was observed in angiosarcoma lesions compared to normal skin following intravenous administration. In conclusion, PVP significantly enhanced the Ce6 concentration in tumors compared with Ce6 alone and increased the therapeutic index of PDT without any side effects in animal model. No serious adverse events were observed in human as well.