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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.