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.     

Solid dispersions based on inulin for the stabilisation and formulation of delta 9-tetrahydrocannabinol.

The aim of this study was to develop a dry powder formulation that stabilises the chemically labile lipophilic Delta(9)-tetrahydrocannabinol (THC), that rapidly dissolves in water in order to increase the bioavailability and that opens new routes of administration. It was investigated whether these aims can be achieved with solid dispersions consisting of a matrix of inulin, an oligo-fructose, in which THC is incorporated. These solid dispersions were prepared by lyophilisation of a solution of THC and inulin in a mixture of water and tertiary butyl alcohol (TBA). Both 4 and 8 wt.% of THC could be incorporated in a glassy matrix of inulin. In the solid dispersions only 0.4-0.5 wt.% of residual TBA was present after storage at 20 degrees C/45% relative humidity (RH) for 7 days. Unprotected THC was completely degraded after 40 days of exposure to 20 degrees C and 45% RH. However, solid dispersions exposed to the same conditions still contained about 80% non-degraded THC after 300 days. Dissolution experiments with tablets compressed from inulin glass dispersion material showed that THC and inulin dissolved at the same rate. Tablets weighing 125 mg and containing 2mg THC were prepared from a mixture of THC containing solid dispersion, polyvinylpolypyrrolidone (PVPP) and mannitol. Dissolution tests revealed that from these tablets 80% of the THC was dissolved within 3 min, which makes them promising for sublingual administration. It was concluded that THC can be strongly stabilized by incorporating it in a matrix of inulin. The aqueous dissolution rate was high which may improve bioavailability.     

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.     

DC calcium lactate, a new filler-binder for direct compaction of tablets

In this paper, a directly compressible form of calcium lactate is introduced as a filler-binder for direct compaction of tablets. Calcium lactate is one of the most important calcium sources and has, in comparison with other organic calcium salts, a good solubility and bioavailability. Two different modifications, calcium lactate trihydrate and calcium lactate pentahydrate are described in the main pharmacopoeias. This paper describes that the compaction properties of calcium lactate pentahydrate (Puracal DC) are much better than those of the calcium lactate trihydrate (Puracal TP). Calcium lactate pentahydrate has better compaction properties than dicalcium phosphate dihydrate, even if lubricated with magnesium stearate. Moreover, as a consequence of its crystalline structure, calcium lactate pentahydrate has a low compaction speed sensitivity. This means that, in combination with its excellent flow properties, calcium lactate pentahydrate is a suitable filler-binder in tablets prepared by high-speed compaction. In a number of formulation examples it will be illustrated that tablets containing calcium lactate pentahydrate as main or additional filler-binder have a short disintegration time and a fast drug release. Directly compressible calcium lactate can be considered as a promising excipient in both pharmaceutical tablets and tablets for the nutraceutical market.     

Inulin as filler-binder for tablets prepared by direct compaction.

The tabletting properties of a number of different amorphous inulin types were investigated. The types varied with respect to chain length, particle size and amount of included air in the particles. Powder flow properties and densities of the different types were investigated. Just as expected, it was found that the flow properties improved with increased particle size of the material. Compactibility was investigated by compression of tablets on a compaction simulator, simulating the compression on high-speed tabletting machines. The bonding capacity of all inulins was high. However, the lubricant sensitivity strongly varied among the different types of inulin. Generally, amorphous materials such as starches are highly lubricant sensitive, because they show ductile behaviour upon compaction. On the other hand, crystalline materials such as dicalcium phosphate dihydrate have a low lubricant sensitivity, because they fragment during compaction. A high lubricant sensitivity was indeed found for amorphous inulins with a low amount of entrapped air. In contrast, the lubricant sensitivity of the amorphous inulin was low when particles containing large amounts of air were compressed. Obviously entrapped air induces fragmentation of the powder particles by which the lubricant film, covering the particles, was destroyed. Tablets prepared from inulin did not disintegrate but they dissolved when incubated in water. The disintegration/dissolution time increased with decreasing chain length of the inulin. The addition of a disintegrant reduced the disintegration time. The somewhat slower dissolution of the longer chain inulin can be an advantage for chewable tablets or lozenges. It was concluded that inulin with large amounts of entrapped air is a good filler-binder and an attractive alternative to commonly used filler-binders.     

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.     

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.     

Outcomes after hand injuries

A 25-year-old male and a 41-year-old male presented at the Emergency Department with a hand injury. Although both patients received immediate surgical care and specialized rehabilitation care, outcomes were better in the first patient, who had sustained the more severe hand injury. Outcomes were influenced not only by injury severity, but also by personal and external factors. Personal factors, such as age, motivation and compliance, were more favourable in the first patient. External factors, such as complications, delayed care, language problems and social problems, mainly affected the second patient, who was less severely injured. As a result, outcomes on all functional levels of the WHO's International Classification of Functioning, Disability and Health (body functions and structure, and activity and participation) were better in the patient with the more severe injury. Specialized hand care is required in hand injuries, but professionals should also be aware that personal and external factors have a substantial influence on outcomes after hand injuries.     

CLSM as Quantitative Method to Determine the Size of Drug Crystals in a Solid Dispersion

Purpose  

To test whether confocal laser scanning microscopy (CLSM) can be used as an analytical tool to determine the drug crystal size in a powder mixture or a crystalline solid dispersion.