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Biomedical subjects

C F Lerk

Publications and source records attributed to C F Lerk.

At least 19 recordsLinked to original sources
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↗
PubMed1987

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 alpha-lactose monohydrate, roller-dried beta-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.

Cellulose↗
PubMed1987

Native starch in tablet formulations: properties on compaction.

Maize, potato, rice and tapioca (cassava) starch were evaluated with respect to their properties on direct compression. Rice starch showed much better compactibility as compared to maize, potato and tapioca starch. Moreover, its binding capacity proved to be almost insensitive to mixing with magnesium stearate. This in contrast to the dramatic decrease in crushing strength of potato starch tablets containing the lubricant. The compactibility of the starches was found to be strongly affected by the equilibrium moisture content of the starches, which is dependent on the relative humidity of the atmosphere under which the powders were stored. All starches showed adequate capacity for water uptake to act as a disintegrant. Rice starch exhibited worst flowability, caused by its fine particle size as compared to the other starches. Granulation of rice starch changed it into a potential filler-binder in tablets prepared by direct compression.

Chemistry, Pharmaceutical↗
PubMed1987

Release and antimicrobial activity of silver sulphadiazine from different creams.

The release and antimicrobial activity of silver sulphadiazine from five different creams were studied: unguentum emulsificans aquosum, unguentum hydrophylicum non ionogenicum, paraffin cream (15 per cent), a homemade preparation and a commercially available preparation (Flamazine). A diffusion cell was used to measure the release and the agar well diffusion technique to determine the antibacterial activity of the silver sulphadiazine released. The paraffin cream (15 per cent) preparation had the highest release rate, followed by the homemade cream and the commercially available cream. The antibacterial activity ran parallel with the release results. This study shows the silver sulphadiazine paraffin cream to be superior to the other four preparations, including the commercially available silver sulphadiazine cream, using release and antibacterial activity as criteria.

Microbial Sensitivity Tests↗
PubMed1986

Studies on tableting properties of lactose. Part III. The consolidation behaviour of sieve fractions of crystalline alpha-lactose monohydrate.

The consolidation and compaction behaviour of sieve fractions of crystalline alpha-lactose monohydrate were studied. From mercury porosimetry measurements tablet pore surface areas were derived. At a certain compaction load it appeared that tablets compressed from small particles were generally stronger and showed a larger surface area than compacts prepared from coarse sieve fractions. By plotting compact strength against pore surface area, a unique linear relationship was obtained. From these results it can be concluded that the actual tablet surface area, being a function of both the initial particle size and applied compaction pressure, is responsible for the compact strength.

Chemistry, Pharmaceutical↗