Henning G. Kristensen

A dynamic in vitro lipolysis model. I. Controlling the rate of lipolysis by continuous addition of calcium.

Lipolysis by pancreatic lipase was investigated with the aim to establish an in vitro lipolysis model, which can be used to investigate the dissolution of poorly soluble lipophilic drug substances at controlled hydrolysis rates. The effects of three experimental parameters -- the concentrations of bile salts and Ca(2+) and the lipase activity -- were investigated. The effect on the rate of hydrolysis of emulsified soybean oil was investigated in experiments in a pH-stat at pH 6.5 and 37 degrees C. The free fatty acids produced by the hydrolysis were titrated at pH 6.5. It was shown that all three investigated parameters influence the initial rate of hydrolysis, whereas only the lipase activity and the concentration of Ca(2+) affect the subsequent stages. It was also shown that the rate of lipolysis can be controlled by the rate of adding Ca(2+). Thus, it is possible to design an in vitro model using readily available and inexpensive materials in which the hydrolysis rate can be controlled by the continuous addition of Ca(2+).

A dynamic in vitro lipolysis model: II: Evaluation of the model

A lipolysis model was characterised and evaluated by investigating the composition of the aqueous phase and the concentration of probucol and danazol in the aqueous phase. Effects of bile salt levels at 5, 10, 20, and 30 mM were investigated. Samples were taken at 0%, 50%, 75% and 95% hydrolysis of the triglycerides, and the aqueous phases were isolated by ultra-centrifugation, whereby the concentrations of bile salts, fatty acids, mono-, di-, triglycerides, and drug substances were measured. At high Ca(2+)-concentrations, bile salts were believed to precipitate with Ca(2+). The concentration of lipolytic products (fatty acids + monoglycerides) was dependent on the bile salt concentration. The ratio between lipolytic product and bile salts was 1.55+/-0.09 (S.D.). This ratio is equivalent to mixed bile salt micelles and vesicles in equilibrium. The aqueous solubility of probucol and danazol was increased in the presence of bile salts. The concentration of danazol in the aqueous phase was dependent on the solubilisation capacity of the aqueous phase. In the case of probucol, the concentration in the aqueous phase was dependent on the partition of probucol between the aqueous phase and the remaining triglyceride phase. This difference between danazol and probucol was attributed to the effect of different lipophilicity.

Melt Granulation in A Laboratory Scale High Shear Mixer

AbstractThe applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.

A Comparison of the Solubility of Danazol in Human and Simulated Gastrointestinal Fluids

Betty Lomstein Pedersen,1,3 Anette Müllertz,1 Dissolution Media Helle Brøndsted,2 and Henning Gjelstrup Ten HIFs and five human gastric fluids (HGFs) were used. Kristensen1 The fluids originated from 13 healthy male and female subjects who had fasted for 10 hours. For two subjects both the intestinal and gastric fluid were included in the study. The method for Received February 17, 2000; accepted April 11, 2000 aspiration has been described in detail by Lindahl et al. (1) and

Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides

The potential for lipidic self-microemulsifying drug delivery systems (SMEDDS) containing triglycerides with a defined structure, where the different fatty acids on the glycerol backbone exhibit different metabolic fate, to improve the lymphatic transport and the portal absorption of a poorly water-soluble drug, halofantrine, were investigated in fasted lymph cannulated canines. Two different structured triglycerides were incorporated into the SMEDDS; 1,3-dioctanoyl-2-linoleyl-sn-glycerol (C8:0-C18:2-C8:0) (MLM) and 1,3-dilinoyl-2-octanoyl-sn-glycerol (C18:2-C8:0-C18:2) (LML). A previously optimised SMEDDS formulation for halofantrine, comprising of triglyceride, Cremophor EL, Maisine 35-1 and ethanol was selected for bioavailability assessment. The extent of lymphatic transport via the thoracic duct was 17.9% of the dose for the animals dosed with the MLM SMEDDS and 27.4% for LML. Also the plasma availability was affected by the triglyceride incorporated into the multi-component delivery system and availabilities of 56.9% (MLM) and 37.2% (LML) were found. These data indicate that the pharmaceutical scientist can use the structure of the lipid to affect the relative contribution of the two absorption pathways. The MLM formulation produced a total bioavailability of 74.9%, which is higher than the total absorption previously observed after post-prandial administration. This could indicate the utility of disperse lipid-base formulations based on structured triglycerides for the oral delivery of halofantrine, and potentially other lipophilic drugs.

The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer

The aim of this study was to prepare by melt agglomeration agglomerates containing solid dispersions of diazepam as poorly water-soluble model drug in order to evaluate the possibility of improving the dissolution rate. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 or Gelucire 50/13 (mixture of glycerides and PEG esters of fatty acids) as meltable binders in a high shear mixer. The binders were added either as a mixture of melted binder and diazepam by a pump-on procedure or by a melt-in procedure of solid binder particles. Different drug concentrations, maximum manufacturing temperatures, and cooling rates were investigated. It was found to be possible to increase the dissolution rate of diazepam by melt agglomeration. A higher dissolution rate was obtained with a lower drug concentration. Admixing the binders by the melt-in procedure resulted in similar dissolution rates as the pump-on procedure. The different maximum manufacturing temperatures and cooling rates were found to have complex effects on the dissolution rate for formulations containing PEG 3000, whereas only minor effects of the cooling procedure were found with Gelucire 50/13. Gelucire 50/13 resulted in faster dissolution rates compared to PEG 3000.

Preparation and purification of cationic solid lipid nanospheres—effects on particle size, physical stability and cell toxicity

Cationic solid lipid nanospheres (SLN) were prepared by the microemulsion technique with polysorbate 80 (Tween 80) and butanol as surfactants. The SLN (diameter 100-500 nm, zetapotential around +15 mV) consisted mainly of stearylamine (SA) and different triglycerides. Three different purification methods, ultrafiltration, ultracentrifugation and dialysis, were investigated and compared with the cellular toxicity and physical stability of the dispersions. The cell toxicity was dependent on both the SLN composition and the purification method. Dialysis was found to easily and efficiently remove excessive surfactant determined by dynamic light scattering (DLS), leading to reduced cell toxicity and increased physical stability of the SLN on storage. The cationic SLN might constitute a promising DNA delivery system.

Dissolution of Hydrocortisone in Human and Simulated Intestinal Fluids

AbstractPurpose. To compare solubility and dissolution rate of hydrocortisonein aspirated human intestinal fluids (HIFs) with simulated intestinalfluids (SIFs) and buffer. Methods. Solubility and flux from a rotating disk of hydrocortisonewere measured. The bile salt content, pH and osmotic pressure weredetermined in HIFs. Results. In fasted state the solubility of hydrocortisone was higher inHIFs than in the buffer and SIFs. The flux of hydrocortisone in HIFswas similar to the flux in the buffer but lower than the flux in SIFs atfasted state. Addition of intestinal surfactants in SIFs increasedsolubility and flux at both fasted and fed state. The increase in solubility wascaused by micelle formation in SIFs. The increase in flux may partlybe explained by increased solubility. The bile salt content of the HIFsdid not correlate with the solubility or the flux but pH in the HIFsseems to have some effect on the components of the HIFs resultingin increased solubility. Conclusions. It is possible to perform comparable dissolution tests inHIFs and SIFs. The lack of correlation between the results in HIFs andthe bile salt content may be explained by the relatively low lipofilicity ofthe model drug.

Prolonged Release Matrix Pellets Prepared by Melt Pelletization II. Hydrophobic Substances as Meltable Binders

Abstract12 meltable substances were studied with respect to their ability to form prolonged release pellets in a melt pelletization process using a laboratory scale high shear mixer. It was found that few substances were able to pelletize a formulation with 12.5% m/m paracetamol and 87.5% m/m calcium hydrogen phosphate. Favourable technical features of glyceryl monostearate were combined with release prolonging features of more hydrophobic substances. Pellets prepared with combinations of glyceryl monostearate and microcrystalline wax demonstrated the slowest release. The release of drug could be varied within wide limits by varying the composition of the binder phase.

Influence of Liquid Bonding Strength on Power Consumption During Granulation in a High Shear Mixer

AbstractA comparison between the effects of different binders on power consumption and -granule growth by granulation in a Fielder PMAT 25 high shear mixer demonstrates that the power consumption is influenced by the intra-granular porosity and the surface tension of the binder solution. It is suggested that the effects are due to a correlation between the power consumption and the strength of mobile liquid bondings in the moist agglomerates. It is shown that the power consumption reflects the change of the intragranular porosity for a particular granulation process with dicalcium phosphate.