Optimization of a formulation for direct compression using a simplex lattice design

In this paper it is demonstrated how the optimum composition of a mixture for direct compression consisting of -lactose monohydrate, roller-dried -lactose and microcrystalline cellulose can be found using a systematic optimization technique. The experiments were chosen according to a simplex lattice design. The results of these experiments were used to fit a mathematical model, which then can predict the properties of all possible mixture compositions and enables a graphic representation of these properties in the form of contour plots. At a level of 4% the effect of three disintegrants (sodium starch glycolate, croscarmellose sodium and crospovidone) on the properties of the tablets compressed from these filler-binders, was evaluated by superimposing the contour plots of the different tablet responses. It was found that all the disintegrants used were effective in this combination of filler-binders. In order to evaluate drug dissolution rate an extra experiment with crospovidone as the disintegrant was performed, in which oxazepam was used as a test drug.     

Controlled Release of Theophylline Monohydrate from Amylodextrin Tablets: In Vitro Observations

Amylodextrin is a linear dextrin and can be produced by enzymatic hydrolysis of the -1,6 glycosidic bonds of amylopectin. Tablets compacted from pure amylodextrin showed good binding properties and did not disintegrate in aqueous media. Extended and decreasing drug release rates were found for tablets of 300 mg with a diameter of 9 mm containing 70% amylodextrin and 30% theophylline monohydrate, when compacted at 5 kN. Almost-constant drug release rates were obtained for these tablets when compacted at 10 or 15 kN. Nearly constant drug release rates were also shown for amylodextrin tablets with a drug load up to 75% compacted at 10 kN. Both release rate and release profile could be adjusted by selecting tablet thickness and incorporation of either lactose as a highly soluble excipient or talc as a hydrophobic excipient.     

The Effect of Parenterally Administered Cyclodextrins on Cholesterol Levels in the Rat

The inclusion complex formation of intravenously administered hydroxypropyl--cyclodextrin and -cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol–cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000–8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol–cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol--cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered -cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl--cyclodextrin after intravenous administration.     

Plasticisation of amylodextrin by moisture: consequences for drug release from tablets

Moisture influences the consolidation behaviour of amylodextrin powders and the porosity and mechanical strength of compacts thereof. The aim of this study is to relate moisture content and compact properties to drug release characteristics of amylodextrin tablets. Therefore, amylodextrin tablets containing theophylline monohydrate were prepared and their release characteristics were studied as a function of moisture content and initial porosity. Drug release from amylodextrin tablets occurs through a leaching mechanism in which cracks are progressively formed in the hydrated part of the matrix leading to almost constant release rates. Small variations in moisture content resulted in large changes of the release rate. A unique relationship between porosity and release rate, which was independent on moisture content and compaction pressure, was observed. Above a critical porosity of 0.075 crack formation was followed by disintegration and fast release. Below this critical porosity, tablets stayed intact despite of the formation of cracks, and sustained release was observed. It is concluded that control over moisture content is essential for the production of amylodextrin tablets with reproducible release characteristics. Using amylodextrin containing 10-17%, moisture, tablets with a constant release behaviour can be obtained if sufficient compaction pressure ( > 300 MPa) is applied. Lubrication of amylodextrin powders reduces the effect of porosity significantly and improves the robustness of amylodextrin tablets as a release controlling excipient in tablets largely.     

Quinolones and colonization resistance in human volunteers

The suppression of alimentary canal flora by the three quinolones nalidixic acid, ciprofloxacin and pefloxacin was investigated in fifteen volunteers. They received the three quinolone compounds in tablet form both uncoated and colon-coated.Escherichia coli suppression was poor under nalidixic acid, but complete under ciprofloxacin and pefloxacin for both administration forms. The indigenous anaerobic flora contributing to the control of aerobicStreptococcus faecalis andCandida albicans in the intestines ('colonization resistance') was not affected by nalidixic acid and pefloxacin, and only slightly by ciprofloxacin. Out of the three quinolone compounds, only colon-coated pefloxacin was associated with a considerable absorption rate at colonie level. Using these criteria of successfulEscherichia coli clearing from the intestinal canal - left the indigenous flora more or less intact (in a 'selective' way) - and a good absorption rate, pefloxacin is found to be superior to ciprofloxacin and nalidixic acid. These results suggest that a colon-coated tablet with a low dose of pefloxacin is a promising administration form in the therapy of recurrent urinary tract infections and diarrhoeal diseases and in the prevention of gut colonization in immunocompromised hosts.     

Preparation,Characterization, and Pharmaceutical Application of Linear Dextrins. II. Complexation and Dispersion of Drugs with Amylodextrin by Freeze-Drying and Kneading

The ability of amylodextrin (a linear dextrin) to act as a complexing agent or as a carrier for solid dispersion was evaluated. Blends of amylodextrin with diazepam or prednisolone were freeze-dried and kneaded at elevated temperatures, respectively. The products were analyzed by DSC, X-ray diffractometry, and FTIR spectroscopy. Complex formation with amylodextrin by freeze-drying was found not to occur for diazepam but for prednisolone at a molar ratio of 1 to 1. The freeze-dried product of diazepam with amylodextrin proved to be a solid dispersion. Solid dispersions were formed by both wet (with ethanol) and dry kneading at elevated temperatures of low-melting drugs such as lidocain, diazepam, and methyl-PABA with amylodextrin. No solid dispersions were obtained for high-melting drugs such as prednisolone and salicylic acid. The results point to the formation of solid dispersions by a melting mechanism during the process of kneading at elevated temperatures of low-melting drugs with amylodextrin.     

Oral controlled release dosage forms. A review

When a drug meets the criteria which make incorporation into a controlled release dosage form rational, a proper dosage form has to be selected. Oral controlled release products, available on the Dutch market, are referred to in discussing the various methods used to control drug release by galenical means in order to achieve a prolonged therapeutic effect. The effects of some physiological variables of the alimentary tract on drug delivery from the various dosage forms, especially with regard to formulation and design, are reviewed.