N. Washington

Determination of baseline human nasal pH and the effect of intranasally administered buffers.

The nose is becoming a common route of drug administration, however, little is known about the pH of the human nasal cavity. Local pH may have a direct effect on the rate and extent of absorption of ionizable compounds and hence this study was performed to investigate normal pH values and whether pH could be manipulated by various buffers. Twelve healthy volunteers participated in a study to measure pH in the anterior and posterior sites of the nasal cavity. Miniature pH electrodes were placed 3 cm apart in the nasal cavity and a baseline was recorded for 30 min once the pH had stabilized. One hundred microlitres of isotonic solution was sprayed into the nostril and the pH was measured for 4 h post-dose. The following five formulations were tested: formulation A--sodium chloride (0.9%) at pH 7.2; formulation B--sodium chloride (0.9%) at pH 5.8; formulation C--Sorensens phosphate buffer (0.06 M) at pH 5. 8; formulation D--Sorensens phosphate buffer (0.13 M) at pH 5.8 and formulation E--formulation as (c) but adjusted to pH 5.0. Each formulation also contained saccharin sodium (0.5%) as a taste marker for nasal clearance. The time at which each subject detected the taste of saccharin was noted. The 30-minute baseline recording prior to administration of the nasal spray formulation demonstrates that there was both considerable intersubject and intrasubject variation in nasal pH. The average pH in the anterior of the nose was 6.40 (+0. 11, -0.15 S.D.) when calculated from H(+) values. The pH in the posterior of the nasal cavity was 6.27 (+0.13, -0.18 S.D.). The overall range in pH was 5.17-8.13 for anterior pH and 5.20-8.00 for posterior pH. Formulation A caused the pH in the anterior part of the nasal cavity to reach a maximum of 7.06 in 11.25 min from the baseline of pH 6.14 (P<0.05). The mean baseline pH was 6.5 for the posterior part of the nose which did not change over the recording period. Formulation B caused the anterior pH to increase from pH 6. 60 to 7.25 within the first minute. This fell back to a mean pH of 7.07 over the first hour which was still significantly above the baseline. It remained at this value for the remainder of the recording period. The initial average posterior pH was 6.32 and again this did not significantly change over the recording period. Formulation C produced a sustained increase in anterior nasal pH from a baseline pH of 6.57-7.12. A small transient decrease was observed in the pH in the posterior of the nose but baseline pH of 6. 6 was re-established within 15 min post dose. Formulation D significantly reduced anterior nasal pH from 6.30 to 5.87 by 30 min reaching a pH of 5.95 by 90 min where it remained for the remainder of the recording period. The posterior baseline pH was 6.3 and introduction of the pH 5.8 buffer caused a slow increase over 90 min to pH 6.6. Formulation E increased anterior pH from 6.1 to 6.7 for the remainder of the recording period. It had an insignificant effect on posterior nasal pH. The mean (+/-S.D.) time to taste saccharin for formulations A to E was 13.42+/-10.21, 14.67+/-8.37, 11.67+/-8.08, 10.08+/-7.6, 9.80+/-6.73 min, respectively. There was no significant difference between the clearance times for the different formulations. In conclusion, average baseline human nasal pH is approximately 6.3. Nasal anterior pH can be decreased when buffers of 0.13 M and above are used. Mildly acidic solutions produce an increase in pH presumably due to reflux bicarbonate secretion. Posterior nasal pH was not altered by administration of any buffer except the 0.13 M buffer at pH 5.8. This produced a rise in posterior pH.

Gastrointestinal transit of a controlled-release pellet formulation of tiaprofenic acid and the effect of food

Abstract The gastrointestinal transit of a controlled-release pellet formulation of tiaprofenic acid has been studied in human subjects. The pellets were labelled with a gamma-emitting radionuclide and their gastric emptying and colon arrival profiles monitored using a gamma camera after two different feeding conditions; light breakfast and heavy breakfast. It is clearly demonstrated that feeding has an important effect upon the gastrointestinal transit profiles. The presence of the heavy breakfast causes a lengthened gastrointestinal time and also a greater spreading of the pellets within the small intestine. As has been found previously, the transit time of the pellets (expressed as time for 50%) to move from pyloric sphincter to ileocaecal sphincter was of the order of 3 h and was independent of the nature of the meal provided.

The effect of inclusion of aluminium hydroxide in alginate-containing raft-forming antacids

Abstract The effect of the inclusion of aluminium hydroxide on the neutralization profiles and raft strength of alginate-based antacid formulations was investigated using in vitro techniques. The results indicate that the aluminium hydroxide remains associated with the raft material and does not neutralize the acid layer below. The physical strength of the raft produced by the formulation on reaction with acid was reduced by the inclusion of aluminium hydroxide.

Effect of dose size, food and surface coating on the gastric residence and distribution of an ion exchange resin

Abstract Ion exchange resin displays prolonged gastric residence and uniform distribution over the gastric mucosa when given in a small volume of water to fasted subjects. The aim of this study was to explore factors which could influence the observed gastric retention, for example the quantity of resin administered, the fed state of the subject, and the surface charge of the resin. The study was performed as a single blind, three-way crossover in 12 healthy volunteers using gamma scintigraphy to visualize the distribution of the resin in the stomach. On the first two occasions each subject received either a 25 mg or 250 mg dose of cholestyramine (an anionic exchange resin) in 1 ml of water. On the last occasion each volunteer received 250 mg of cholestyramine coated with the inert polymer ethylcellulose, to determine if the gastric residence of the resin was influenced by the surface properties of the particles. For all formulations, half of the subjects were fed 4 h after dosing to determine the effects of inducing a fed pattern of motility on the gastric retention of the resin. Gastric retention was measured as the area under the stomach activity–time curve (AUC). Median AUC values (relative units) for the 25 mg, 250 mg and polymer coated 250 mg doses were 139.6, 199.6 and 146.0 respectively, for fasted subjects and 164.1, 256.9 and 176.1 for fed subjects. Approximately 20% of the resin persisted in the stomach for the entire 6 h of the study in every case, and this was distributed evenly throughout the fundus, body and antrum. Statistical analysis of the data showed no significant differences between the gastric emptying and distribution of any of the data sets. It can be concluded that the prolonged gastric residence and uniform distribution of ionic resins is not influenced by the dose size and that the binding of the dose to the mucosa is sufficiently strong to retain the dose during feeding 4 h after administration. The mechanism by which resin becomes mucoadherent is not clear; however, these results indicate that it is unlikely to be due to a charge-based attraction.

The gastrointestinal transit of a controlled release formulation of indomethacin

Abstract The gastrointestinal transit of a controlled release indomethacin tablet has been evaluated in vivo in a group of six fasted and fed subjects using the technique of gamma-scintigraphy. The product was similar in its gastrointestinal transit behaviour to other pharmaceutical dosage forms; emptying of the tablet from the stomach was slowed by the presence of food but transit through the small intestine was not affected by feeding conditions. In vivo the tablet underwent a process of gradual dissolution and diffusion followed by complete dispersion. The bioavailability of indomethacin from this preparation was not affected by the presence of food.

An investigation into the efficacy of the pectin based anti-reflux formulation-Aflurax.

The properties of the new pectin-based anti-reflux agent Aflurax (Ferrosan) were studied in vitro and in vivo. Aflurax had a significantly higher in vitro raft strength than the placebo which was matched to the active except for the pectin (4.66+/-2.10 and 0. 22+/-0.04 g, respectively). In the modified Rossett and Rice test, the pectin raft remained above pH 3 for 130 min, whereas the pH in the acid phase remained unchanged. A modification to the stirring speed of the Rossett and Rice test was required to obtain a neutralisation profile for the placebo. The neutralisation profiles for the Aflurax and placebo were the same since both contained 5 mEq of base per tablet. In the in vivo study, subjects were randomly assigned to two groups, which either received radiolabelled food and unlabelled formulation, or unlabelled food and radiolabelled formulations. A pH probe was passed naso-gastrically and placed 5 cm from the cardia, and a small gamma detector was placed on the chest wall, coincident with the pH probe. The subjects received the test meal after an overnight fast. The pectin formulation or placebo was administered 30 min later. Each part of the study was performed as a single-blind two-way cross over with the active versus placebo. The reflux of radiolabel and acid was monitored for three hours postprandially. Aflurax reduced the H(+) concentration (total refluxed hydrogen ion index for Aflurax=3.5 x 10(3)+/-2.1 x 10(3), placebo=29 x 10(3)+/-16 x 10(3)) and amount of radiolabelled food reaching the oesophagus (total refluxed count index of food in counts x 1000 min(-1) Aflurax=19.2+/-2.3, placebo=525+/-423). The mean time for which the oesophageal pH fell below pH 4 was 2.58+/-1. 0 and 0.86+/-0.4 minutes for the placebo and Aflurax groups, respectively. The total amount of radiolabelled formulation which reached the oesophagus was 1000+/-660 for the placebo and 621+/-580 for the Aflurax.

Evaluation of ‘raft-forming’ antacid neutralizing capacity: in vitro and in vivo correlations

Abstract pH telemetry has been employed to measure the in vivo neutralization-time profile of two antacid formulations, ‘Asilone Suspension’ and ‘Gaviscon Liquid’, in man. The results from this investigation were compared with those obtained in the Rossett and Rice in vitro test (1954) of acid neutralizing capacity. For both antacids, the test gave a poor prediction of the duration of action in vivo. The in vitro test was modified to improve the correlation with the in vivo results, both for raft-forming and conventional antacids.

Dry powder dosing in liquid vehicles: ocular tolerance and scintigraphic evaluation of a perfluorocarbon suspension

The ocular tolerance and precorneal disposition of 99mTc-labelled sterile carbon-perfluorodecalin (PFD) and carbon-aqueous suspensions were examined in a cohort of healthy volunteers. Formulations were prepared in PFD or saline using charcoal particles, radiolabelled with [99mTc]diethylenetriaminepentaacetic acid (DTPA) under GMP conditions. Colloidal silicon dioxide was used as a suspending agent. Ocular tolerance was examined following the instillation of each formulation to the eyes of 12 volunteers. The precorneal distribution of both formulations in man was monitored using gamma scintigraphy. Dynamic and static data acquisitions were taken over a period of 150 min after dosing. Carbon particulates suspended in PFD did not show any irritation to the eye. Administration of PFD formulation in man produced a significant increase in ocular retention over a saline formulation (mean residence time (MRT)=157+/-42 and 0.29+/-0.08 min, respectively, P=0.0001). Distribution of the carbon in man followed the same pattern as in a previous reported study in animals. The carbon deposited uniformly along the lid margin in the case of the PFD vehicle, whereas it agglomerated following dosing in the saline vehicle and was ejected from the eye. The novel non-aqueous vehicle system is able to significantly improve the ocular retention of charcoal particles in man and provides a unique distribution of the particles in the eye, which suggests a potential for the PFD system for the treatment of periocular diseases.

The neutralization capacity of magnesium trisilicate BP and magnesium trisilicate mixture BP

Abstract The in vitro neutralization properties of magnesium trisilicate mixture BP and its ingredients have been examined using the Rossett and Rice test. It is concluded that the inclusion of the principal component, magnesium trisilicate, in the mixture is unwarranted due to the failure to demonstrate a significant neutralizing action. This appears to be due to the extremely slow rate of reaction of this compound with hydrochloric acid.