Biomedical subjects

C F Lerk

Publications and source records attributed to C F Lerk.

At least 19 recordsLinked to original sources

PubMed2001

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.

Lactic Acid↗

PubMed2001

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<x(w)<0.40 was studied by conventional and modulated DSC. Elastic modulus and yield stress were determined from compressive stress-strain experiments. Compaction behaviour was studied at 3 and 300 mm/s using a compaction simulator. RESULTS: The T(g) of amylodextrin-water blends showed a smooth reduction with increasing x(w), equalling room temperature at x(w)=0.19. Experimentally obtained T(g) values were close to temperatures as predicted by the Gordon-Taylor/Kelley-Bueche model and the modified Couchman-Karasz model. The elastic modulus decreased steeply between x(w)=0.17 and 0.23. Compaction experiments showed that moisture facilitated consolidation due to increasing powder compressibility and reduced compact relaxation. However, at x(w)=0.23, compressibility was reduced and relaxation significantly higher due to the rubbery character of this powder. Consequently, the lowest tablet porosities were obtained around x(w)=0.15. Although decreasing porosities enhanced tablet strengths, the maximum obtainable tablet strengths decreased with moisture due to reduced particle bonding and lowering of the elastic modulus. CONCLUSION: Moisture largely affects the visco-elastic and compaction characteristics of amylodextrin. Hence, control over moisture content is essential to produce tablets with reproducible porosity, strength and dissolution characteristics.

Calorimetry, Differential Scanning↗

PubMed2000

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.

Bronchodilator Agents↗

PubMed1998

Influence of plasticizers on tableting properties of polymers.

This study relates tablet formation with relaxation properties of two polymers on the basis of the stress-deformation curve. The mechanical properties of the polymers were varied by changing tableting temperature, adding varying amounts of plasticizer, and incorporating a monomer with plasticizer effect on the polymer chain. The crucial parameter appeared to be the difference between the glass transition temperature and the tableting temperature. This temperature difference was found to determine the amount of energy stored during densification. The energy is manifested as the stress relaxation propensity of the material. Large stress relaxation yields porous and consequently weak tablets. At a low temperature difference (i.e., tableting temperature is much lower than the glass transition temperature), the amount of stored energy is large. An increase in tableting temperature, or a decrease in glass transition temperature, yields a decrease in stored energy as a result of a decrease in yield strength. Consequently, production of less porous and stronger tablet is possible. However, if the tableting temperature is higher than the glass transition temperature, the stress relaxation propensity of the deformed polymers is extremely high because the elastic modulus of the materials is low under these circumstances. This results is porous and even capped tablets. From the data it is concluded that, independent of the type of polymer and the method of plasticizing, compaction at a temperature of about 20 K under the glass transition temperature yields circumstances for which the amount of stored energy has a minimum. Consequently, tablet porosity has a minimum and tablet strength has a maximum. These circumstances are created by changing both the tableting temperature and the glass transition temperature of the powder.

Algorithms↗

PubMed1997

Effect of compaction temperature on consolidation of amorphous copolymers with different glass transition temperatures.

PURPOSE: The purpose of this study was to relate the combination of glass transition temperature (Tg) and temperature of measurement with the mechanical and compaction properties of some test materials. METHODS: Copolymers with different Tg'S were synthesised by free radical copolymerisation of methyl methacrylate with lauryl methacrylate. Elastic moduli were measured by dynamic mechanical analysis at different strain rates and temperatures. Compaction experiments were performed at different compaction speeds and temperatures. RESULTS: The difference between temperature of measurement and Tg appears to determine both elastic modulus and yield strength completely. They both decrease with decreasing difference between temperature of measurement and Tg and increase with strain rate. At temperatures of measurement higher than the Tg the elastic modulus is extremely low because the materials behave as rubbers. Consequently, the amount of energy stored during compaction decreases when the compaction temperature approaches the Tg and increases with strain rate. When the compaction temperature is higher than the Tg, the amount of stored energy is extremely large. The compaction experiments show that the final tablet porosity is completely determined by stress relaxation phenomena. Consequently, the final tablet porosity follows exactly the same relation as that of stored energy. CONCLUSIONS: The final tablet porosity is unequivocally determined by the amount of stored energy. This implies that tablet production at a temperature of about 20 K under the glass transition temperature of the material yields tablets with minimum porosity.

Glass↗

PubMed1994

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 alpha-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.

Chemical Phenomena↗

PubMed1994

Controlled release of paracetamol from amylodextrin tablets: in vitro and in vivo results.

Amylodextrin is a suitable excipient for the design of solid controlled-release systems. The release of paracetamol from tablets containing 30% drug and 70% amylodextrin was studied in vitro and in vivo. In vitro dissolution profiles showed almost-constant drug release rates during 8 hr, when measured in 0.05 M buffer, pH 6.8. Peroral administration of the tablets to man showed almost-constant paracetamol plasma levels up to 14 hr, as compared to fast absorption and fast elimination of a reference paracetamol solution. The plasma profiles of eight volunteers demonstrated a small intersubject variability during the first day after tablet administration. Increasing variability and decreasing plasma levels during the second day were caused by excretion of tablets from the bodies. Cumulative input as a function of time showed near-zero-order drug release during the first day. The in vivo results indicate that amylodextrin tablets are not hydrolyzed by alpha-amylase, present in the gastrointestinal tract.

Acetaminophen↗

PubMed1994

Preparation, characterization, and pharmaceutical application of linear dextrins. III. Drug release from fatty suppository bases containing amylodextrin.

Drug release from fatty suppository bases containing a solid dispersion of diazepam with amylodextrin or a complex of prednisolone with amylodextrin was analyzed in a flow-through model. Being present as a suspension in the fatty base, particles of complex or solid dispersion are transported to the lipid-water interface by sedimentation. After entering the aqueous phase they partially dissolve. The suppositories showed increased drug release compared with the corresponding suppositories containing drug only. Because of the partial solubility of amylodextrin, drug release was lower than the release from drug-cyclodextrin complexes. Use of the soluble fraction of amylodextrin for both the solid dispersion and the complex further enhanced drug release, but it was still below that of drug-cyclodextrin complexes.

Dextrins↗

PubMed1993

Preparation, characterization and pharmaceutical application of linear dextrins. I. Preparation and characterization of amylodextrin, metastable amylodextrins, and metastable amylose.

The linear dextrin amylodextrin was prepared by enzymatic hydrolysis from waxy maize. Four metastable amylodextrins were prepared by complexation with different volatile organic compounds. All products showed partial dissolution into water at room temperature, because of dissolution of molecules with a lower DP. X-ray diffractometry revealed a helical conformation with six glucose units per turn for amylodextrin and metastable amylodextrins prepared with small molecules, and a helical conformation with seven glucose units per turn for metastable amylodextrins prepared with larger molecules. All metastable amylodextrins showed a helix with reduced distance between two turns as compared to amylodextrin. Metastable amylose, prepared from Amylose V, showed a helical conformation again with a reduced distance between two turns compared to Amylose V. FTIR analysis indicated a more flexible conformation for Amylose V and metastable amylose than for the amylodextrins.

Amylose↗

PubMed1993

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.

Calorimetry, Differential Scanning↗

PubMed1991

The effects of cyclodextrins on the disposition of intravenously injected drugs in the rat.

Naproxen and flurbiprofen form complexes with hydroxypropyl-beta-cyclodextrin; with stability constants of 2207 and 12515 M-1, respectively. However, only small fractions of the drug remain complexed when the drug-cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl-beta-cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1991

The effect of parenterally administered cyclodextrins on cholesterol levels in the rat.

The inclusion complex formation of intravenously administered hydroxypropyl-beta-cyclodextrin and beta-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-beta-cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered beta-cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl-beta-cyclodextrin after intravenous administration.

Animals↗

PubMed1990

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.

Animals↗

PubMed1990

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.

Biotransformation↗

PubMed1990

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.

Biosensing Techniques↗

PubMed1990

The pharmacokinetics of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin in the rat.

Hydroxypropyl-beta-cyclodextrin was analyzed by HPLC using postcolumn complexation with phenolphthalein and negative colorimetric detection, with a detection limit of 20 micrograms/ml. The pharmacokinetics of beta-cyclodextrin and of hydroxypropyl-beta-cyclodextrin were studied after intravenous administration to permanently cannulated rats. The pharmacokinetic behavior of both cyclodextrins was similar to that of inulin, showing rapid distribution over extracellular fluids. Elimination occurred through glomerular filtration. When a dose of 200 mg/kg beta-cyclodextrin was administered the elimination rate was decreased, probably as a result of nephrotoxicity of beta-cyclodextrin. Within 24 hr after administration most of the cyclodextrin dose was recovered unchanged in urine. After oral administration, only insignificant amounts of intact beta-cyclodextrin were absorbed from the gastrointestinal tract.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1988

Formation and antimicrobial activity of complexes of beta-cyclodextrin and some antimycotic imidazole derivatives.

Complex formation between beta-cyclodextrin and six antimycotic imidazole derivatives has been studied. The solubility of all drugs was increased in the presence of beta-cyclodextrin. The smallest increase (approx. 5-fold) was observed for miconazol, and the largest increase (approx. 160-fold) was observed for bifonazol. Apparent 1:1-complex constants were measured and found to decrease in the order: bifonazol greater than ketoconazol greater than tioconazol greater than miconazol greater than itraconazol greater than clotrimazol. The complexes appeared to possess a low, if any, antimicrobial activity. Measurement of inhibition zone sizes, with four test organisms was used to study the release of the antimycotic drugs from topical preparations. The antimycotic drugs were more readily released from topical preparations containing beta-cyclodextrin than from the same vehicles without beta-cyclodextrin. The rationale of beta-cyclodextrin addition to antimycotic topical preparations is discussed.

Anti-Infective Agents↗

PubMed1988

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.

Chemical Phenomena↗