Rectal versus oral absorption of diflunisal in man

Rectal absorption of diflunisal from various dosage forms was studied in man. The rectal dosage forms included fatty and macrogol suppositories, an aqueous suspension and solutions with various solvents in order to achieve complete dissolution of diflunisal. A comparison was made with an orally administered suspension. The plasma concentrations of diflunisal were measured by means of HPLC analysis after a single dose of 250 mg diflunisal in a cross-over study in 7 volunteers.Compared with oral administration, rectal absorption conditions are limited as a consequence of the poor solubility characteristics of diflunisal. Therefore attempts were made to improve absorption conditions by varying the nature of the rectal dosage form. The addition of alkali and solvents such as polyethylene glycol and glycofurol, did result in an increase of the rate of absorption, whereas the bioavailability 8 h after administration did rise up to 80% as compared with oral dosing. In the case where suppositories are employed, a fatty vehicle rather than a water-soluble base should be chosen in order to stimulate the driving force for absorption. It is concluded that 500 mg diflunisal suspended in a 4 ml fatty mass results in peak plasma concentrations comparable with an oral dose of 250 mg diflunisal.     

Preliminary study on the absorption profile after rectal and oral administration of methadone in human volunteers

Methadone is a potent, long acting narcotic analgesic which can be orally administered due to its almost complete bioavailability. There is a growing interest in the rectal route of administration in the case of acute postoperative or chronic malignant pain. Since virtually no data were available on the rectal absorption profile of methadone in man, plasma concentrations of methadone were determined by means of HPLC analysis after a single dose of 10 mg methadone HCl in a cross-over pilot study in five volunteers. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. Compared with oral dosing, the extent of rectal absorption from an aqueous solution was almost 80% up to 8 h after dosing. Although the mean peak concentration and the AUC_0-8h was significantly lower (p < 0.01), no marked difference in t_max was observed: 2.8 and 3.1 h respectively. Rectal absorption conditions of methadone from fatty suppositories (3 ml) were found to be less favourable. The peak plasma concentration was only reached 3–4 h after administration, whereas the relative bioavailability up to 8 h after dosing ranged from 35–58%. This rate-limiting absorption pattern may be due to the critical solubility properties of methadone HCl at physiological pH.     

Manipulation of rectal absorption rate of phenytoin in man

Rectal absorption of phenytoin and its sodium salt from various dosage forms was studied in man. The rectal dosage forms included fatty suppositories, an aqueous suspension and solutions with various solvents in order to achieve complete dissolution of phenytoin. The plasma concentration of phenytoin was measured by means ofHplc analysis after a single dose of 200 mg phenytoin in a cross-over study in eight volunteers. A comparison was made with oral administration. Compared with oral administration rectal absorption conditions of phenytoin from fatty suppositories or aqueous suspensions were found to be extremely unfavourable. Although the addition of alkali and glycofurol increased the rectal absorption, absorption only occurred with an appreciable rate during the first 30 minutes after administration. This in contrast to a rectal solution using polyethylene glycol 600 as a solvent which did produce a slow but continuous absorption over at least 8 hours. Relative bioavailability after this period of time was calculated to be 50%. We conclude that it is in principle possible to improve the rectal absorption rate and also the bioavailability of phenytoin by increasing the solubility of this drug with non-absorbable agents.In honour of ProfessorHuizinga on the occasion of his retirement.     

Rectal absorption of metronidazol from polyethylene glycol suppositories

The rectal absorption of metronidazol from an aqueous suspension, a fatty suppository and three different polyethylene glycol suppositories was studied in healthy volunteers and compared with absorption from an oral solution. Rectal absorption was found to be rather slow for all suppositories. Of all rectal dosage forms, the polyethylene glycol suppositories gave the highest peak plasma levels and the highest relative bioavailability. Compared with oral administration, a relative bioavailability of 80% could be obtained.     

Absorption rate and bioavailability of valproic acid and its sodium salt from rectal dosage forms

Summary Rectal and oral absorption of valproic acid and its sodium salt by man were compared to explore the possibility of rectal administration of the drug. The plasma concentration of valproic acid was measured by gas chromatography after a single oral dose of sodium valproate 600 mg, and after single rectal doses of sodium valproate 600 mg and valproic acid 520 mg, in a cross-over study in 7 volunteers. The rectal dosage forms included fatty suppositories and aqueous solutions. Compared with oral administration, rectal absorption of sodium valproate from an aqueous micro-enema was fast and complete. The free acid was absorbed more rapidly from fatty suppositories than was the sodium salt. The absorption rate from the rectum increased with the dose of valproic acid. Both findings are consistent with a diffusion — absorption mechanism based on the pH-partition hypothesis. Differences in the chemical composition of the fatty suppository base were not reflected in differences in absorption rate and relative bioavailability. No essential difference in absorption rate was observed if volunteers remained lying or sitting during the experiment. Rectal dosing with valproic acid 520 mg dissolved in 4 ml suppositories, twice a day resulted in steady-state plasma concentrations of 50 to 100 µg · ml^–1, within the therapeutic range.Data have been presented in: F. Moolenaar, Ph. D. Thesis, Groningen, The Netherlands     

Biopharmaceutics of rectal administration of drugs in man

Rectal absorption of acetylsalicylic acid and its calcium salt was studied in man and compared with oral absorption. Plasma concentrations of acetylsalicylic acid and salicylic acid were measured by means ofHplc analysis, after a single dose of acetylsalicylic acid (500 mg) and after single rectal doses of acetylsalicylic acid (500 mg) and calcium acetylsalicylate (640 mg) in a cross-over study in 8 volunteers. The rectal dosage forms included fatty suppositories and aqueous solutions. Compared with oral administration rectal absorption of acetylsalicylic acid can be equally rapid, if the volume and the pH of the aqueous micro-enema was optimized (20 ml, pH 4.0). Rectal absorption of calcium acetylsalicylate occurred very slowly. If fatty suppositories were used smaller particles favoured the rate of acetylsalicylic acid absorption. Compared with oral administration absorption from the optimized suppository dosage form proceeded significantly (P < 0.05) slower. For all rectal dosage forms, the extent to which acetylsalicylic acid reached the general circulation intact, was smaller than after oral administration. In honour of ProfessorPolderman on the occasion of his retirement.     

Biopharmaceutics of rectal administration of drugs in man 7. Absorption rate and bioavailability of phenobarbital and its sodium salt from rectal dosage forms

In this report it will be shown that rectal administration of phenobarbital and its sodium salt can be looked upon as an alternative route of administration.Plasma phenobarbital concentrations were measured in 6 volunteers after a single oral dose (219 mg) of sodium phenobarbital and after single rectal doses of phenobarbital (200 mg) or sodium phenobarbital (219 mg). In the case of the rectally administered aqueous dosage forms of phenobarbital no distinct difference in absorption rate occurred whether the sodium salt or the free acid was used. Rectal administration of both types of micro-enemas results in absorption which is less rapid than after oral administration of the sodium salt. However, the final and total absorption of phenobarbital and its sodium salt after 6.5 h is practically complete, compared with oral administration. The in vitro release of phenobarbital from fatty suppositories using a coarse powder (125–250 μm) of sodium phenobarbital and with a fine powder (<20 μm) of phenobarbital showed marked differences. The rectal absorption profile of the aqueous and fatty dosage forms of sodium phenobarbital in vivo was quite similar. A much slower absorption rate was observed if the free acid was used in the fatty suppository dosage form.     

Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs

Absorption and disposition characteristics of carprofen were compared in the dog after intravenous, oral, and rectal administrations. Rectal formulations included an aqueous solution and a suppository. Single doses of 100 mg carprofen were given in a cross-over design and plasma concentrations of unchanged drug were determined by HPLC. Plasma concentration-time profiles could be adequately described after intravenous and extravascular administrations by tri-and biexponential functions, respectively. After intravenous applications the basic disposition parameters could be determined: mean (+/- S.D.) elimination half-life was about 11.7 (+/- 3.1) h; volume of distribution ranged from 0.12 to 0.22 l kg-1 and total plasma clearance was about 0.017 +/- 0.003 l h kg-1. After oral dosing, carprofen was rapidly absorbed (time of maximum concentration: 0.83 +/- 0.61 h) and comparison with the intravenous solution indicated complete bioavailability. After rectal administration, the rate of absorption evaluated through tmax and calculation of mean absorption times was always slower than after oral dosing. Relative bioavailabilities of the drug from the suppository were about 20 per cent lower than from rectal solutions. No significant difference in rates of absorption of carprofen from rectal solution and suppository was seen; this allowed the conclusion that drug release from the semi-solid dosage form was not the rate-limiting step in carprofen absorption from the suppository. From the present study, it is concluded that rectal administration of carprofen offers an alternative to the oral route of drug intake.     

Rectal bioavailability of lidocaine from a suppository and a slow release preparation in man

In a previous investigation it was shown that the systemic availability of lidocaine in humans following rectal administration of an aqueous solution was about twofold higher than after oral administration. Most likely this was due to a partial avoidance of hepatic ‘first-pass’ metabolism. In the present study the systemic availability of two different rectal dosage forms of lidocaine was examined. Six healthy volunteers received in a balanced cross-over design a rectal capsule with slow release granules and a suppository, both containing 300 mg lidocaine as lidocaine. HCl. Plasma concentrations were measured for 8 h after drug administration by capillary gas chromatography. The mean rectal systemic availability of the two preparations was not significantly different: 49% (suppository) and 54% (capsule), when compared to the results obtained in a previous investigation after intraveneous administration. Early defaecation occasionally caused a loss of still unabsorbed drug. Mean bioavailability of the rectal aqueous solution was 70%. As expected, the absorption from the suppository was more rapid than from the capsule: the mean peak times were 122 min and 195 min respectively (p < 0.05). The mean maximum plasma concentrations were comparable: 0.70Μg/ml (suppository) and 0.69Μg/ml (capsule) respectively. These results confirm the previous findings that rectal administration of lidocaine results in a higher systemic availability than oral administration, but they are at the same time rather variable with the dosage forms studied.     

Biopharmaceutical evaluation of ketoprofen following intravenous, oral, and rectal administration in dogs

The influence of the hydrophilicity of three suppository bases on the rectal absorption of ketoprofen was studied. Absorption characteristics of ketoprofen were compared after intravenous, oral, and rectal administrations of 100 mg of drug given in a crossover design to five dogs. Rectal formulations included an aqueous solution and three suppository formulations. After oral dosing, ketoprofen was rapidly absorbed (time of maximum concentration, tmax: 0.83 +/- 0.61 h), and a comparison with the intravenous solution indicated a complete bioavailability of 0.90 +/- 0.10. After rectal administration, the rate of absorption, as evaluated with tmax and mean absorption time, was always slower than after oral dosing. A high variability was observed in the plasma concentrations obtained with suppository formulations; bioavailability values were approximately 20% lower than those from the oral solutions. No statistical difference in bioavailability and peak concentrations between the three suppository formulations was observed. Time of peak concentrations, mean absorption times, and fractions of the dose absorbed 6 h post administration did not show a difference in rate of ketoprofen absorption from the three suppository formulations. This study did not reveal a relationship between rate and extent of ketoprofen rectal absorption and the hydrophilicity of the suppository bases tested.     

Apparent absorption kinetics of micronized griseofulvin after its oral administration on single- and multiple-dose regimens to rats as a corn oil-in-water emulsion and aqueous suspension.

This investigation was designed to quantitate and compare in the rat the oral absorption characteristics of micronized griseofulvin from a corn oil-in-water emulsion dosage form containing suspended drug and a control aqueous suspension after single-dose (50 mg/kg) and multiple-dose (50 mg/kg every 12 hr for five doses) administrations. The time course of intact drug in the plasma of all animals was best described by a one-compartment open model with apparent zero-order absorption. In contrast to that observed with the aqueous suspension, the onset of drug absorption after single-dose administration of the corn oil emulsion was significantly delayed. This difference disappeared upon multiple dosing of the two dosage forms, with the mean onset being quite rapid in both cases. Administration of a single dose of the antibiotic as the corn oil emulsion resulted in considerable increases in the maximum plasma levels of griseofulvin and in the duration, relative extent, and uniformity of drug absorption compared to those observed after administration of the control aqueous suspension. The potentiating effects of the lipid on drug absorption persisted on multiple dosing but at a somewhat reduced level.     

The bioavailability of cefpodoxime proxetil tablets relative to an oral solution

The bioavailability of cefpodoxime proxetil tablets relative to an oral solution of cefpodoxime proxetil in a sucrose/alcohol/citric acid vehicle was studied in 11 healthy volunteers in a randomized, crossover study. Fasted subjects took one cefpodoxime proxetil 100 mg tablet or 50 mL of a 2 mg mL^?1 cefpodoxime proxetil oral solution on two separate occasions. In a third study period, all subjects took a 100 mg dose of the oral solution with a high-fat meal to investigate the effect of food on cefpodoxime proxetil absorption from the oral solution. Serial blood samples were obtained over a 24h period, and urine was collected for 48h after dosing. Cefpodoxime concentrations in plasma and in urine were determined using HPLC methods. The bioavailability of cefpodoxime proxetil tablets relative to the oral solution was 82%, as determined from AUC ratios. There was no difference in the rate of cefpodoxime absorption between dosage forms. Food had no effect on the extent of drug absorption from the oral solution but did result in delayed absorption. These results suggest that complete dissolution of cefpodoxime proxetil is critical for optimal bioavailability.     

Development of oral extended release formulations of 6‐hydroxybuspirone

Reducing the maximum plasma concentration whilst maintaining the exposure was shown to ameliorate adverse events following the oral administration of 6‐hydroxybuspirone. This observation, along with a desire to provide for once daily dosing of this compound, provided the basis for the development of an extended release formulation. Hydrophilic matrix tablets based on hydroxypropyl methylcellulose and containing citric acid to provide for an acid microenvironment were prepared and evaluated by in vitro drug release studies and in vivo pharmacokinetic and scintigraphic studies using samarium oxide (¹⁵³Sm) labelled dosage forms. The dosage forms were found to release the contained drug by a predominantly diffusion mechanism and the release rate was relatively independent of environmental pH. Following administration of the extended release formulations to volunteers, comparative pharmacokinetic data indicated that the extended release formulations provided for a reduction in the maximum plasma concentration of 64–70% relative to that provided by the same dose given as an oral solution, whilst maintaining exposure relative to the oral solution. By examination of absorption curves derived by Wagner‐Nelson analysis of pharmacokinetic data it was noted that drug release in vivo correlated well with drug release observed in vitro and no marked change in rate of absorption was noted when dosage forms were located in and releasing drug in the colon. The robust control of drug release seen in vitro translated to a good in vivo performance. Copyright © 2012 John Wiley & Sons, Ltd.     

Plasma concentrations following single doses of morphine sulfate in oral solution and rectal suppository

Plasma concentrations of morphine and morphine-3-glucuronide (morphine's major metabolite) were determined following single 10-mg doses of morphine sulfate in oral solution and rectal suppository. Ten patients with pain secondary to cancer were given a single 10-mg dose of oral morphine sulfate in an oral solution or rectal suppository on sequential days. Blood samples were collected at time zero and periodically for 4.5 hours after administration. Plasma concentrations of morphine and morphine-3-glucuronide were determined using liquid chromatography with electrochemical detection. Higher mean concentrations of morphine were achieved with the rectal suppository than with the oral solution at all time points, and the overall mean plasma morphine concentration for the entire 4.5-hour period was significantly higher for the rectal suppository than for the oral solution. There were no significant differences between dosage forms in mean morphine-3-glucuronide concentrations at individual time points or over the entire period. A single dose of morphine sulfate in a rectal suppository was better absorbed than in an oral solution. Further studies are needed to compare the clinical efficacy of these dosage forms under steady-state conditions.     

Rectal absorption of flecainide acetate

Summary The rectal absorption of flecainide from an aqueous solution, a fatty suppository and a polyethyleneglycol suppository was studied in one patient with supraventricular tachycardia (Wolff-Parkinson-White syndrome) refractory for oral anti-arrhythmic treatment.Rectal absorption was found to be fast (t_1/2abs=1 h) and complete when flecainide was administered as a solution (relative bioavailability 100%).Flecainide was poorly absorbed from a fatty suppository. The polyethyleneglycol suppository gave absorption with a relative bioavailability of 80% and t_{1/2 abs}=1.2 h.     

Pharmacokinetics and bioavailability of ergoloid mesylates

The pharmacokinetics and bioavailability of ergoloid mesylates following single administrations of various dose levels (3-9 mg), dosage forms (oral swallow and sublingual tablets, solution) and under different dosing conditions (fasted, with meal) were studied in young healthy volunteers. Male and female subjects showed a similar rate and extent of bioavailable ergoloid after drug treatment. The absorption of ergoloid using either the tablet dosage forms or the drug administered as a solution was rapid, with peak levels of about 60-80 pg ml-1 mg-1 dose achieved after 0.6 to 1.3 h. The elimination half-life for ergoloid in plasma was 2-5 h. Administration of drug with food had no effect on the extent of absorption (AUC) but lowered the absorption rate. This resulted in a reduction of (by 25 per cent) and delay in (by 1 h) achieving peak levels (Cmax). Increasing the ergoloid dose caused a proportional increase in the AUC, but a smaller than proportional increase for Cmax. The tablet formulations provided similar AUCs as the solution; the objective of the sublingual tablet formulation to provide improved bioavailability over the swallow tablet via circumvention of first-pass metabolism was therefore not realized. Transient decreases in blood pressure after ergoloid treatment paralleled the plasma level profiles. Higher ergoloid levels were paired with the larger pressure decreases.     

Pharmacokinetics of buflomedil after various dosage forms

The pharmacokinetic disposition of buflomedil was compared in humans after oral administration of solution, tablets and film tablets. Six healthy male volunteers received a single oral dose of the three different dosage formulations. Blood and urine samples were taken before dosing and at selected times over 24 h and 72 h, resp., after dosing. The concentration of the drug in samples was measured by gas-chromatography with nitrogen detector. The absorption of buflomedil was faster after solution administration, while other plasma parameters did not show any major differences. Also the amount of drug excreted in urines was higher with solution dosing.     

Enhanced enteral bioavailability of vancomycin using water-in-oil-in-water multiple emulsion incorporating highly purified unsaturated fatty acid

The aim of this study was to evaluate the potential of an emulsion incorporating unsaturated fatty acids to improve the mucosal absorption of poorly absorbed drugs from rat intestinal loops in situ, using a water-in-oil-in-water (W/O/W) multiple emulsion. Vancomycin hydrochloride (VCM) was used as a model drug with low oral bioavailability. The entrapment efficiency of VCM in the emulsion was approximately 60% and remained constant over storage for 1 month at 4 degrees C. The emulsion incorporating C18 unsaturated fatty acids or docosahexaenoic acid (DHA) markedly enhanced VCM absorption after colonic and rectal dosing. The effectiveness of DHA on VCM colonic absorption improvement was the same as that of oleic acid, and less than that of linoleic and linolenic acids. For rectal dosing, bioavailability was similar among various emulsions, in the range 40-50%. The effect of the emulsion incorporating oleic acid or DHA on improving VCM enteral bioavailability was not increased proportional to the incorporated amount. The electrical resistance of membranes was not changed by the incorporation of various fatty acids in emulsions. Our results indicated that W/O/W emulsions incorporating C18 unsaturated fatty acid or DHA were useful carriers for improving the absorption of poorly absorbable drugs via the intestinal tract without gross changes to tight junction function.     

Application of Radiotelemetric Technique in Evaluating Diclofenac Sodium Absorption After Oral Administration of Various Dosage Forms in Healthy Volunteers

A radiotelemetric technique with the Heidelberg capsule (HC) was used to improve the quality of data generated in a bioavailability study involving an enteric-coated (EC) formulation. Further, changes in plasma levels of the drug from other dosage forms were related to changes in the pH environment as determined by the HC. Eight healthy male subjects received the following treatments, 15 min after a light breakfast, according to a randomized, four-way crossover design: (A) HC and 75 mg of a diclofenac sodium aqueous buffered solution; (B) HC and one 75-mg Voltaren EC tablet; (C) HC and one 100-mg Voltaren slow-release (SR) tablet; and (D) HC alone. Each treatment was separated by a 1-week washout period. Two additional subjects subsequently received Treatment B only. Multiple peaks were observed in the drug plasma level–time profiles for the buffered aqueous solution which, in all cases, occurred before gastric emptying of the HC. The multiple peaks were not observed for the Voltaren SR tablet, but a variable absorption lag time occurred which coincided with the gastric residence time of the SR tablet. For the EC tablet the variability of individual plasma level–time profiles was drastically reduced when the time after dosing was adjusted to coincide with gastric emptying of the HC. Finally, the lag time between gastric emptying of the EC tablet and the onset of drug absorption was consistently at 1 hr for all subjects. This lag time was longer than the in vitro disintegration or dissolution times measured under USP conditions.     

Pharmacokinetics of salicylic acid following administration of aspirin tablets and three different forms of soluble aspirin in normal subjects

The pharmacokinetic profile of an innovative formulation of soluble aspirin (l-ornithine acetylsalicylate, ldB 1003) was compared with that of conventional tablets and two other soluble dosage forms (d, l-lysine acetylsalicylate and a buffered effervescent formulation of acetylsalicylic acid) after administration of single oral doses in six normal volunteers. All soluble forms showed a rapid absorption profile, peak plasma salicylic acid levels being attained after about 30 min on average and without statistically significant differences among the solutions tested. As compared to the soluble formulations, acetylsalicylic acid given as tablets resulted in slower absorption, with peak plasma salicylic acid levels being reached more than 1 h after dosing. Despite these differences in time course of plasma level profiles, the extent of absorption was similar for all formulations. Apart from the potential advantages in terms of improved gastric tolerability, the increased rate of absorption of aspirin solutions is therapeutically useful whenever a rapid onset of action is required. In this respect, the kinetic pattern of the innovative formulation compares favourably with that of other available soluble dosage forms.