Development of a potentially wearable glucose sensor for patients with diabetes mellitus: design and in-vitro evaluation.

A potentially wearable glucose sensor was developed, consisting of an oxygen electrode as detector and a dynamic enzyme perfusion system as selector. The selector is a hollow fibre, which can be placed subcutaneously and dialyses glucose from tissue fluid. In this design the problems of enzyme instability and oxygen limitation might be circumvented. The sensor measures glucose reliably for over two weeks, provided a new 10 ml syringe containing a glucose oxidase solution is connected to the system each day.

Intratumoural administration of cisplatin in slow-release devices. I. Tumour response and toxicity.

In this study we investigated the effect of the incorporation of cisplatin in slow-release systems on tumour response and animal toxicity after intratumoural (i.t.) administration. Solid slow-release rods with incorporated cisplatin were prepared either from starch or from three different polyether-hydrogel formulations. In vitro release rates from these rods were widely different. With the starch system, approximately 100% release was obtained in 2 h. For the hydrogel formulations, release was approximately 100% in 1 day for a formulation with 40% water uptake (T3), 45% within 4 days for a formulation with 14% water uptake (T2) and 8% within 4 days for a formulation with 4% water uptake (T1). The slow-release rods containing graded amounts of cisplatin were implanted i.t. in s.c. RIF1 murine tumours. The i.t. administration of cisplatin in starch rods did not reduce animal toxicity or increase tumour response relative to i.t. injections of cisplatin in solution. For the hydrogel rods, the tumour response and animal toxicity for a given dose of cisplatin decreased with decreasing release rate. Higher doses of cisplatin could therefore be delivered with the slower-releasing hydrogel formulations. The slowest-release hydrogel rods (T1) had very little effect on either tumour (growth delay) or host (animal weight loss), even at cisplatin doses 8 times that tolerated as an i.p. injection. The fast (T3)- and intermediate (T2)-release hydrogel rods resulted in dose dependent tumour growth delays that were longer than those obtained with i.p. or i.t. administration of cisplatin. The highest response, a tumour growth delay of 55 days, was obtained with the intermediate-release hydrogel rods (T2) at a cisplatin dose of 40 mg/kg. Analysis of tumour growth delay for a given level of toxicity indicated that the intermediate-release formulation (T2) was slightly better than the fast-release formulation (T3) and confirmed the therapeutic advantage of i.t. implants over systemic therapy.

Effect of molecular weight and glass transition on relaxation and release behaviour of poly(DL-lactic acid) tablets.

Different molecular weight grades of poly(DL-lactic acid) were applied as release controlling excipients in tablets for oral drug administration. The role of molecular weight and glass transition in the mechanism of water-induced volume expansion and drug release of PDLA tablets was investigated. Modulated differential scanning calorimetry (MDSC) was used to determine the glass transition temperature of both dry and hydrated PDLA samples. The absorption rate and total amounts of sorbed water by the polymer were determined by dynamic vapour sorption (DVS). Expansion behaviour of PDLA tablets was measured using thermal mechanical analysis (TMA). At 95% relative humidity all molecular weight grades of PDLA sorbed 1.1-1.3% w/w water, as was determined with DVS. MDSC showed glass transition temperature reductions of 10-11 degrees C for all molecular weight grades of PDLA in water. Volume expansion studies using TMA showed that the molecular relaxation time and equilibrium porosity of the tablets increased with molecular weight. The mean relaxation time increased exponentially with the temperature interval T(g)-T. The onset temperature of shape recovery of hydrated tablets was approximately 8 degrees C lower than for dry samples. Drug release was only slightly affected by molecular weight. It is concluded that volume expansion of compressed PDLA tablets is related to the glass transition behaviour, originates from water-induced and thermally stimulated shape memory behaviour and is therefore highly dependent on the molecular weight of PDLA.

Cyclodextrin-facilitated bioconversion of 17 beta-estradiol by a phenoloxidase from Mucuna pruriens cell cultures.

After complexation with beta-cyclodextrin, the phenolic steroid 17 beta-estradiol could be ortho-hydroxylated into a catechol, mainly 4-hydroxyestradiol, by a phenoloxidase from in vitro grown cells of Mucuna pruriens. By complexation with beta-cyclodextrin the solubility of the steroid increased from almost insoluble to 660 microM. The bioconversion efficiency after 72 hr increased in the following order: freely suspended cells (0%), immobilized cells (1%), cell homogenate (6%), phenoloxidase preparation (40%). Mushroom tyrosinase converted 17 beta-estradiol, as a complex with beta-cyclodextrin, solely into 2-hydroxyestradiol, with a maximal yield of 30% after 6-8 hr. Uncomplexed 17 beta-estradiol was not converted at all in any of these systems.

Theoretical analysis of the release of drug from completely dissolving carriers containing drug particles.

The approach of "controlled supply of slow-release particles" is evaluated for a dissolving carrier system containing drug particles. Drug dissolution from this system is calculated after solving a convolution integral. The effects of geometry and relative dissolution time between drug particles and carrier device on drug dissolution kinetics are considered. Minima in the deviation of the dissolution profiles from linearity as a function of relative dissolution time are found. The impacts of geometry on the minima are discussed. Incorporation of a second system of isometric drug particles in an isometric carrier shows less deviation from constant-release kinetics when suitable values of the parameters affecting drug release are used in the calculations. A substantially constant rate of release of drug can be realized for a system of two carriers, each containing "slow-release" drug particles. The initial deviation from linearity in the sigmoidally shaped profile of drug dissolved in time from one of the two carriers is eliminated by the release of dissolved drug from the second carrier. About 80% of the drug content is dissolved at a constant rate by the combination of the two carriers.

Effect of microcrystalline cellulose on liquid penetration in and disintegration of directly compressed tablets.

The penetration of isooctane and water into tablets of microcrystalline cellulose, dibasic calcium phosphate dihydrate, spray-crystallized maltose-dextrose, and blends of microcrystalline cellulose with one of the other excipients were studied. The isooctane penetrations occurred according to the Washburn equation and were not affected by the presence of 0.5 or 1.0% magnesium stearate. The inhibition of aqueous penetration into tablets resulting from hydrophobic magnesium stearate was less pronounced for vehicles like dibasic calcium phosphate, which exhibited extensive brittle fracture under compression. Microcrystalline cellulose tablets, both with and without magnesium stearate, exhibited extremely fast aqueous penetration even at low porosities, caused by breaking of the hydrogen bonds and subsequent widening of the pores. Ratios between water uptake and original pore volume up to 20 were obtained for microcrystalline cellulose tablets. This unique property was, however, suppressed by the presence of fast dissolving and highly soluble excipients like dextrose, resulting in an antagonistic disintegration behavior of tablets compressed at pressures over 10,000 N/cm2. Improved disintegration properties were obtained by blending microcrystalline cellulose with an insoluble vehicle such as dibasic calcium phosphate dihydrate.

Contact angles and wetting of pharmaceutical powders.

Contact angles of pharmaceutical powders were determined by the h-epsilon method, which consists essentially of measuring the maximum height of a drop of liquid fomed on a presaturated compact of the material. Determinations with aspirin as the test material indicate that the measured value is independent of the particle size of the powder and the porosity of the cake. The method was extended to include determinations on mixed powder systems. The results show that the hydrophobic material dominates with large particle-size powders; with small particle sizes, a linear relationship between the cosine of the contact angle of the mixed system and the proportion of the components is obtained. Results are presented for a wide variety of materials of pharmaceutical interest.

Interaction of tablet disintegrants and magnesium stearate during mixing I: Effect on tablet disintegration.

The effect of magnesium stearate on the disintegration of tablets was studied. Three different preblends, containing a slightly or a strongly swelling disintegrant, were mixed before compression with magnesium stearate for different time periods. The results show that a strongly swelling disintegrant, such as sodium starch glycolate in contrast to potato starch, can reduce the deteriorating effect of hydrophobic lubricants on tablet disintegration. However, the interaction between magnesium stearate and potato starch or sodium starch glycolate and the resulting differences in disintegration characteristics can be masked by the use of disks in the USP disintegration apparatus.

Contact angles of pharmaceutical powders.

Contact angles of pharmaceutical powders were determined by measuring the maximum height of a drop of a saturated solution on a presaturated compact of the material. The results for a series of drugs are presented.

Effect of hydrophilization of hydrophobic drugs on release rate from capsules.

The release of poorly soluble hydrophobic drugs from capsules can be improved significantly by the creation of a hydrophilic surface by intensive mixing of the hydrophobic drug with a small amount of a solution of a hydrophilic excipient. This technique was introduced previously for the production of microgranules. The data presented indicate that the hydrophilic material is mechanically distributed over the hydrophobic surface. The creation of hydrophilic capillaries in a capsule or tablet allowed the rapid penetration of the dissolution fluid, resulting in a dispersion of well-wetted particles, so that the maximum surface area of the powder was exposed to the dissolution medium. Moreover, hydrophilization of hydrophobic drugs has the important benefit that the release rate from capsules is independent of the surface tension of the dissolution medium.

In vitro and in vivo availability of hydrophilized phenytoin from capsules.

The effect of phenytoin hydrophilization on the liquid penetration rate into prepared plugs, on the disintegration time, on the in vitro release rate, and on in vivo absorption in humans was studied. Hydrophilization was performed by intensive mixing of the hydrophobic drug with a small amount of methylcellulose solution. Liquid penetration into the treated plugs was independent of the liquid wetting potency and extremely high compared to the pure drug plugs. Analogous results were obtained for the disintegration time and in vitro release rates from capsules loaded with pure and treated drug. A bioavailability study in seven healthy volunteers showed immediate absorption of the treated drug but a 1-hr absorption lag time for the pure drug.

Plasticisation of amylodextrin by moisture. Consequences for compaction behaviour and tablet properties.

PURPOSE: Amylodextrin, a starch-based controlled release excipient, spontaneously absorbs moisture during storage. The aim of this study was to investigate plasticisation of amylodextrin by moisture and its effect on compaction and tablet characteristics. METHODS: The glass transition temperature (T(g)) of amylodextrin powders with moisture fractions (x(w)) 0.070

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.

Effect of dehydration on the binding capacity of particulate hydrates.

The binding capacities of alpha-D-glucose dehydrated at temperatures from 60-135 degrees C increased with increasing temperature of dehydration.