Anko C. Eissens

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

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

The effects of cyclodextrins on drug absorption II. In vivo observations

Complex formation of diazepam and of naproxen with β-cyclodextrin results in increased aqueous solubility of the drug. The complex stability constants found were 179 and 2146 M−1, respectively. To study the effect of complex formation of drugs with β-cyclodextrin in vivo, micro-enemas containing diazepam or naproxen with and without β-cyclodextrin were administered to human volunteers. Plasma levels of the drug were determined for the investigation of the absorption of the two drugs. The results demonstrated that absorption neither of cyclodextrin nor of the drug-cyclodextrin complex took place, and that a decrease in the rate of absorption of the drug did not occur when administered as the drug-cyclodextrin complex. The absence of absorption deceleration was explained by the fact that complexed drug is displaced from the complex by lipids in the mucus adjacent to the absorption membrane. The ability of mucus and bile samples to displace eomplexed drug was shown in vitro in displacement studies with phenolphthalein. Especially bile was shown to possess a high capacity for displacement. The micro-enemas in which all drug was dissolved through complexation showed much faster absorption as compared with those in which the drug was suspended.

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

Naproxen and flurbiprofen form complexes with hydroxypropyl-β-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-β-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.

A new generation of starch products as excipient in pharmaceutical tablets. I. Preparation and binding properties of high surface area potato starch products

A new pharmaceutical excipient with a high binding capacity was prepared from potato starch by enzymatic degradation, followed by suitable dehydration of the precipitated and filtered retrograded starch to produce high specific surface area products. Thermal dehydration methods like drying at room or elevated temperature and spray-drying resulted in particulate solids with low specific surface area, as measured by nitrogen adsorption, and low compactibility. Both freeze-drying and chemical desiccation, like washing with ethanol or acetone, produced powders with strongly increased specific surface area and increased binding capacity. The compactibility of the final products showed a positive correlation with the specific surface area, changing at high surface areas into constant compactibility. Moreover, the binding capacity appeared to increase with the moisture content of the products.

A new generation of starch products as excipient in pharmaceutical tablets. II. High surface area retrograded pregelatinized potato starch products in sustained-release tablets

Abstract A new linear short-chain starch product was prepared by gelatinization of potato starch followed by enzymatic degradation, precipitation (retrogradation) and filtration. A high specific surface area was subsequently created by washing with ethanol or acetone or freeze-drying. Tablets compressed from a mixture containing the starch product and 30% theophylline at a force of at least 15 kN showed no disintegration and an almost constant (zero-order) sustained drug release. The delivery from these non-porous tablets proved to be a swelling-controlled solvent-activated mechanism, as was confirmed by the slow penetration of a solvent front into the tablet. Drug release proved to be not affected by the incorporation of magnesium stearate into the tablet or the presence of α-amylase in the dissolution medium, both features in contrast to similar tablets compressed from conventional pregelatinized starches, which were prepared by gelatinization followed directly by thermic dehydration. A specific surface area of 1.5 m2/g proved to be a prerequisite for the starch product to control drug release. A high surface area (linear long-chain) amylose product showed a sustained but less linear release profile. Branched short and long-chain products with a high surface area produced disintegrating tablets and are therefore not able to control drug release.

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.

Design and Fungicidal Activity of Mucoadhesive Lactoferrin Tablets for the Treatment of Oropharyngeal Candidosis

Lactoferrin (Lf) is a potential drug candidate for the treatment of oropharyngeal Candida infections. However, for an effective therapeutic treatment an appropriate dosage form is required. Therefore a mucoadhesive tablet for buccal application was developed. Tablets of sufficient strength could be produced on high speed tabletting machines, but they could only be obtained when the protein contained at least 7% moisture. The tablet contained sodium alginate both for its release-controlling properties as well as for its mucoadhesive properties. Furthermore, phosphate buffer was added to keep the pH of the saliva in the mouth within the range of 6.5 to 7.5. In this pH range, Lf has shown to have its highest activity against Candida growth inhibition. The tablet formulation containing Lf had the same antifungal properties as compared with Lf alone, because in most cases identical inhibitory concentrations were observed against several clinical isolates of Candida albicans and Candida glabrata. In human volunteers the tablets, containing 250 mg Lf and placed in each pouch, were able to keep the Lf concentration in the saliva at effective levels for at least 2 hr, while the pH of the saliva remained within the desired range. We concluded that the developed mucoadhesive tablet can improve the therapeutic efficacy of Lf and that it is suitable for further clinical research.

A new generation starch product as excipient in pharmaceutical tablets. III. Parameters affecting controlled drug release from tablets based on high surface area retrograded pregelatinized potato starch

This paper describes the general applicability of a new pregelatinized starch product in directly compressible controlled-release matrix systems. It was prepared by enzymatic degradation of potato starch followed by precipitation (retrogradation), filtration and washing with ethanol. The advantages of the material include ease of tablet preparation, the potential of a constant release rate (zero-order) for an extended period of time and the possibility to incorporate high percentages of drugs with different physicochemical properties. Constant release profiles are the result of solvent penetration into the tablet. For theophylline as test drug, constant release profiles could be realized up to a drug content of 75%. This illustrates the possibility to control the release of highly dosed drugs. Release rates from retrograded pregelatinized starch tablets can be enhanced or decreased to the desired profile by different parameters, like geometries of the tablet, compaction force and the incorporation of additional excipients. For procaine HCl it is demonstrated that larger tablets show slower release rates. The incorporation of soluble excipients like lactose and mannitol results for paracetamol in enhanced release rates. The delivery of bases and their salts can be modified by the incorporation of organic acid or alkaline excipients, as is demonstrated for lidocaine and procaine HCl.

β-Cyclodextrin as an excipient in solid oral dosage forms: In vitro and in vivo evaluation of spray-dried diazepam-β-cyclodextrin products

Abstract Diazepam-β-cyclodextrin and diazepam-lactose products were prepared by spray-drying. Complex formation could be demonstrated by differential scanning calorimetry and by application of a so-called “ether-wash” method, for diazepam-β-cyclodextrin but not for diazepam-lactose. Intrinsic dissolution rates were measured using a rotating disc method. The results indicated that, for the drug tested, complexation played only a minor role in dissolution rate enhancement. Both the processing of the drug and the excipient as well as the solubility and amount of the excipient used seemed to be rate-determining factors. Release rates from tablets and capsules were measured using the USP paddle method. For the capsules an enhancement of the dissolution rate by complex formation of the drug with β-cyclodextrin, was only found when low stirring rates were used (20 rpm). The difference in dissolution rate, as obtained at 50 and 20 rpm, can be explained by the presence of an aggregate at the bottom of the beaker at low stirring rates. In the microenvironment around the aggregate the solubility of the drug is enhanced by complex formation. Absorption experiments in human volunteers showed also an increased absorption of diazepam by β-cyclodextrin complexation.

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.