A.J.M. Schoonen

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.

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.

RELEASE OF DRUGS FROM FATTY SUPPOSITORY BASES .1. RELEASE MECHANISM

Abstract A model for drug release from fatty suppository bases is presented that explains in vitro measurements on drugs with various physicochemical characteristics, such as paracetamol (slowly dissolving in water) sodium salicylate (rapidly dissolving in water) and salicylic acid (soluble in lipid). The in vitro results are compared with in vivo experiments on rectal absorption in man. Results indicated that for suspensions of all the drugs investigated, dissolution takes place at the interface between the suppository base and the surrounding fluid. The release process therefore includes a flow of particles in the suppository base into the direction of the interface and a flow of solute away from the interface. Either of these flows may be rate limiting dependent on the water solubility of the drug, and may determine the effect of concentration and particle size on release rate.

The effects of cyclodextrins on drugs absorption. I. In vitro observations

A two-phase transfer system, water with organic solvent, was used to investigate the effect of cyclodextrins on transport of dissolved lipophilic drugs from the aqueous to the organic layer. Four model drugs, diazepam, medazepam, n-butyl-p-aminobenzoate and n-pentyl-p-aminobenzoate were used. Stability constants of different cyclodextrin complexes were determined by a phase solubility technique or by a spectral displacement technique. It was found that the first-order transport rate constants of the drugs were hardly affected by complexation with β-cyclodextrin. This phenomenon could be explained by displacement of the drug from the cyclodextrin complex by organic solvent near the interface. This process results in a unique system which has a low concentration of free drug in the bulk of the aqueous layer, whereas near the interface a relatively high concentration of free drug exists. It could be demonstrated that the properties of the organic solvent also influenced the transport rate of complexed drug.

Release of drugs from fatty suppository bases II. A rate-limiting interfacial process

Abstract In this report the effect of particle size on the release rate of sodium salicylate (a highly water-soluble drug) from fatty suppository bases is studied. In vitro it could be shown by comparing sedimentation measurements and release measurements that a rate-limiting process which is operating on the lipid side of the interface is causing the particle size effect. An equation is proposed describing the release flow as a function of particle size. It is shown that the time needed for the drainage of liquified lipid between a particle and the interface, a process which is essential for the drug to arrive at its dissolution site, is of the same order of magnitude as the time required for a wetted particle of a highly water-soluble drug to dissolve in an aqueous phase. This may imply that, in addition to the dissolution process, the drainage effect under certain conditions could become rate-limiting in the release of drugs from suppositories and thus for rectal absorption rate. Although the drainage time for a single particle layer appeared to be rather independent of particle size, reduction of particle size leads to an increase in the number of layers and consequently to a summation of drainage times for the same weight of drug. In vivo it is shown that probably an increase in ‘concentration viscosity’ (increasing the concentration of particles in the base) does not have a negative effect on absorption rate from the rectum, whereas an increase in the ‘fluid viscosity’, does have a negative effect on absorption rate for suppository bases and liquid-paraffin enemas. Since the drainage time is not influenced by the concentration of particles in the base but only by the viscosity of the lipid phase while the bulk transport of particles through the base is influenced by both effects, it is concluded that in line with in vitro data the drainage time of particles determines the release flow of highly water-soluble drugs also in vivo.

Biopharmaceutics of rectal administration of drugs in man: 4. Absorption rate and bioavailability of paracetamol from fatty suppositories

The rectal absorption of paracetamol after administration of fatty suppositories was studied in six human subjects after single doses (500 and 1000 mg) of the drug, using plasma paracetamol concentrations.Rectal absorption rate was found to be strongly dependent upon the particle size of the drug suspended in the suppository base.In agreement with studies after rectal administration of aqueous suspensions of paracetamol, rectal absorption rate of paracetamol was dependent upon the volume of the fatty vehicle, rather than on the concentration of the drug under study.No differences in absorption rate and bioavailability could be detected between Cocoa butter and Witepsol H 15 suppositories with paracetamol.

Biopharmaceutics of rectal administration of drugs in man II. Effect of particle size on absorption rate and bioavailability

Summary Particle size of readily water-soluble drugs has a significant influence on the release rate from a fatty suppository base in vitro. In a rectal investigation this phenomenon was studied in ten healthy volunteers, by using sodium benzoate as a test drug. The absorption process of benzoate was followed by determination of urine levels of hippurate. After insertion of suppositories containing a coarse powder (sieve fraction 125–250 μm), the absorption rate was significantly faster during 60 min as compared with a micronized powder ( The influence of particle size of slightly soluble drugs (in this study benzoic acid) on the absorption rate proved to be much less than in the case of readily water-soluble drugs. In the case of a micronized fraction the spreadability of the suppository mass can favour the absorption process. As compared with the sodium salt, benzoic acid was absorbed more rapidly and with less inter-individual variation from a fatty base; this finding is in agreement with the pH-partition hypothesis. In spite of all differences in absorption rate, the relative bioavailability of all rectal dosage forms in this study was the same (95% confidence).

The influence of pH on rectal absorption of sodium benzoate studied in man by rectal lumen perfusion

The influence of pH on rectal absorption of sodium benzoate in man was studied by means of a rectal lumen perfusion method and compared with in vitromeasurements on diffusional transport of sodium benzoate across an octanol/water interface. For nonbuffered solutions of benzoate in vitro,it was shown that mass flux across an octanol/water interface occurs in agreement with the pH-partition model. In vivohowever, mass flux increases less with decreasing pH of unbuffered perfusate than is anticipated on the basis of the pH-partition model. Probably an alkaline flow across the rectal mucosa into the lumen is present as a physiological neutralization mechanism. In contrast, buffered solutions of benzoate show a linear relationship between mass flux and decreasing pH in vitroas well as in vivo.The effect of buffer on the concentration profile of benzoic acid is qualitatively explained. It is shown that an alkaline flow across the rectal mucosa only slightly influences absorption of benzoic acid from strongly buffered solutions in the rectal lumen. It is concluded that the use of strong buffers in rectal solutions induces a drastic effect on the pH of the boundary layer, an effect not seen for unbuffered solutions. This phenomenon does not invalidate the pH-partition hypothesis but can be explained by it.

Dissolution of acetaminophen in a single pore and its relevance for dissolution of tablets

Abstract Dissolution of acetaminophen from single pores is investigated in which the pore walls are prepared from specially grown crystals of acetaminophen. Dimensions of pores are measured during dissolution. It is found that a minimum pore size is needed to start pore growth. Above this minimum size, pore growth is proportional to pore width and an increasing height decreases pore growth. There is an effect on pore growth for different orientations of crystal faces constituting the pore wall, and pore shape can change to a cylindrical form. Crystals forming high and narrow pores dissolve with the highest rate at the entrance of the pore, whereas low and wide pores grow with the highest rate at their closed end. It is concluded from these results that centrally in the pore there is an ascending flow of fresh fluid and a descending flow of solute near the pore walls. It is the resistance to flow of the ascending fresh fluid in the pore that determines pore growth. It is shown that the postulated flow regimen for pores may also have some relevance for dissolution behaviour of tablets.

Effect of suppository bases on rectal absorption rate of drugs

Thein vitro release rate andin vivo absorption rate from various suppository bases was measured for benzoic acid (soluble in lipid, moderately soluble in water) and its sodium salt (very soluble in water, insoluble in lipid). Differences in the absorption rate due to a supposed unequal spreading of the basein vivo could not be detected.Micronised fractions of sodium benzoate were absorbed at the same rate from the various bases, indicating that the transport of the particles through the bases and across the lipid-water interface, which is rate limiting in this case, is not influenced by the chemical composition of the base. Absorption of a coarse fraction of sodium benzoate was significantly faster from Witepsol H 15 and Estarinum B suppository bases than from cocoabutter and Massuppol.It is concluded that in the case of sodium benzoate an interfacial resistance between the suppository base and the rectal fluid is present. This is probably caused by a combined effect of the aggregated state of the coarse sodium benzoate particles and an elastic emulsion layer formed at the interface of cocoabutter and Massuppol, since a coarse size fraction of sodium salicylate did not show this effect.