The influence of the degree of esterification on the release characteristics of in situ gelling pectin formulations for oral sustained delivery of paracetamol.

The aim of this study was to examine the effect of a change of the degree of esterification of pectin on the in situ gelation and release characteristics of 1.5% (w/v) pectin solutions over a wide pH range. Formulations of pectin with degrees of esterification of 9% (DE9) and 31% (DE31) containing complexed calcium ions formed gels in vitro at pH 1.2 as a consequence of cross-linking of the pectin chains by free calcium ions released from the complex. In vitro release of paracetamol from these gels was diffusion controlled. A sustained release of paracetamol was observed following oral administration of pectin DE9 and DE31 formulations to gastric acidity-controlled rats at pH 2.5 but only with DE9 formulations at pH 5.5. Examination of the stomach contents confirmed effective in situ gelation of pectin DE9 formulations at a gastric pH of 6 but there was no evidence of the gelation of pectin DE31 formulations at this pH.

Oral liquid in situ gelling methylcellulose/alginate formulations for sustained drug delivery to dysphagic patients.

BACKGROUND: Elderly patients with swallowing dysfunction may benefit from the oral administration of liquid dosage forms with in situ gelling properties. AIM: We have designed in situ gelling liquid dosage formulations composed of mixtures of methylcellulose, which has thermally reversible gelation properties and sodium alginate, the gelation of which is ion-responsive, with suitable rheological characteristics for ease of administration to dysphagic patients and suitable integrity in the stomach to achieve a sustained release of drug. METHOD: The rheological and gelation characteristics of solutions containing methylcellulose (2.0%) and sodium alginate (0.25-1.0%) were assessed for their suitability for administration to dysphagic patients. The gel strength and in vitro and in vivo release characteristics of gels formed by selected formulations were compared using paracetamol as a model drug. RESULTS: Mixtures of 2.0% methylcellulose and 0.5% alginate containing 20% d-sorbitol were of suitable viscosity for ease of swallowing by dysphagic patients and formed gels at temperatures between ambient and body temperature allowing administration in liquid form and in situ gelation in the stomach. In vitro release of paracetamol from 2.0% methylcellulose/0.5% alginate gels was diffusion-controlled at pH 1.2 and 6.8. Measurement of plasma levels of paracetamol after oral administration to rats of a 2.0% methylcellulose/0.5% alginate formulation showed improved sustained release compared to that from 2.0% methylcellulose and 0.5% alginate solutions and from an aqueous solution of paracetamol. CONCLUSIONS: Solutions of mixtures of methylcellulose and alginate in appropriate proportions are of suitable consistency for administration to dysphagic patients and form gels in situ with sustained release characteristics.

In situ gelling formulation based on methylcellulose/pectin system for oral-sustained drug delivery to dysphagic patients.

BACKGROUND: Oral-sustained release gel formulations with suitable rheological properties have been proposed as a means of improving the compliance of dysphagic and geriatric patients who have difficulties with handling and swallowing oral dosage forms. AIM: We have modified the rheological and release properties of thermally reversible methylcellulose solutions by admixture with pectin, the gelation of which is ion-responsive, with the aim of formulating an in situ gelling vehicle suitable for oral-sustained drug delivery. METHOD: Gels formed by solutions containing methylcellulose (1.0-2.0%) and pectin (0.5-2.0%) were assessed for suitable gel strength, and in vitro and in vivo release of paracetamol. RESULTS: Addition of 1.5% pectin to a 2.0% methylcellulose formulation containing 20% d-sorbitol and calcium ions in complexed form increased the gel strength and provided a formulation with a suitable viscosity for ease of swallowing by dysphagic patients. Gels formed in situ after oral administration of this formulation retained their integrity in the rat stomach for sufficient time for sustained release to be achieved. In vitro release of paracetamol from methylcellulose, pectin, and methylcellulose/pectin gels was diffusion-controlled. Plasma levels of paracetamol after oral administration to rats (gastric pH 2.6 and 5.5) of a solution including 2.0% methylcellulose/1.5% pectin showed improved sustained release compared with that from both 2.0% methylcellulose and 1.5% pectin solutions. CONCLUSIONS: The addition of suitable concentrations of pectin to methylcellulose solutions produces in situ gelling formulations with suitable viscosity for administration to dysphagic patients and improved sustained release characteristics.

Carrageenan gels for oral sustained delivery of acetaminophen to dysphagic patients.

We have designed gel formulations for the oral administration of acetaminophen with suitable rheological characteristics for ease of administration to patients with swallowing difficulties and sufficient integrity in the stomach to achieve a sustained release of this drug. Gels formed by agar and ι-carrageenan were assessed for suitable gel strength and in vitro and in vivo release characteristics. Comparison of 1.5% ι-carrageenan gel with 0.5% agar gel demonstrated improved sustained release properties of the ι-carrageenan gel. Gel formed by ι-carrageenan has suitable rheological and sustained release characteristics for potential use as vehicles for oral delivery of drugs to dysphagic patients.

In situ gelling xyloglucan/alginate liquid formulation for oral sustained drug delivery to dysphagic patients.

BACKGROUND: The oral administration of liquid dosage forms of suitable consistency and with sustained release characteristics may provide a means of improving the compliance of geriatric patients who experience difficulties in swallowing conventional solid dosage forms. AIM: We have designed and evaluated liquid preparations for administration to dysphagic patients, composed of aqueous mixtures of xyloglucan, which has thermally reversible gelation characteristics, and sodium alginate, which has ion-responsive gelation characteristics. METHOD: The gelation and in vitro and in vivo release characteristics of liquid formulations containing appropriate concentrations of xyloglucan and sodium alginate with mannuronate/guluronate ratios of either 0.5 or 0.8 were assessed. RESULTS: Aqueous mixtures of 1.5% xyloglucan and 0.5% alginate had suitable viscosities for ease of swallowing and appropriate gelation temperatures (approximately 33 degrees C) to ensure in situ gelation following oral administration. The in vitro release of paracetamol at pH 5.0 from gels formed by these formulations and also by a 1.5% xyloglucan solution was diffusion-controlled. Plasma levels of paracetamol after oral administration to gastric-acidity controlled rats (pH 5) of a solution containing 1.5% xyloglucan/0.5% alginate showed that a more sustained release was achieved from the gels formed by the in situ gelation of this formulation compared with that of a 1.5% xyloglucan solution. Visual observation of the contents of the rat stomach after oral administration showed that the inclusion of alginate in the xyloglucan solutions was effective in reducing gel erosion, so sustaining drug release. CONCLUSIONS: Liquid formulations of xyloglucan and sodium alginate in appropriate proportions are of suitable consistency for ease of administration to dysphagic patients and form gels in situ in the rat stomach capable of sustaining the release of paracetamol over a 6-hour period.

Preparation and evaluation of gel formulations for oral sustained delivery to dysphagic patients.

BACKGROUND: Oral sustained release gel formulations may provide a means of administering drugs to dysphagic and geriatric patients who have difficulties with handling and taking oral dosage forms. AIM: We have designed gel formulations for the oral administration of paracetamol with suitable rheological characteristics for ease of administration to patients with swallowing difficulties and sufficient integrity in the acidic environment of the stomach to achieve a sustained release of this drug. METHOD: Gels formed by gelatin, agar, gellan, pectin, and xyloglucan were assessed for suitable gel strength and in vitro and in vivo release characteristics. RESULTS: Gellan (1.5% w/v) and xyloglucan gels (1.5% w/w) had acceptable gel strengths for ease of swallowing and retained their integrity in the rat stomach sufficiently well to sustain the release of paracetamol over a period of 6 hours. Comparison of 1.5% xyloglucan gels with a commercially available preparation with identical paracetamol concentrations demonstrated improved sustained release properties of the xyloglucan gels. CONCLUSIONS: Gels formed by gellan and xyloglucan have suitable rheological and sustained release characteristics for potential use as vehicles for oral delivery of drugs to dysphagic patients.

In situ gelling xyloglucan/pectin formulations for oral sustained drug delivery.

This study has examined the gelation and release characteristics of mixtures of xyloglucan, which has thermally reversible gelation characteristics, and pectin, the gelation of which is ion responsive, with the aim of formulating an in situ gelling vehicle suitable for oral sustained drug delivery. An investigation of the effect of the inclusion of pectin (0.75% (w/w)) on the rheological properties of gels formed from solutions of xyloglucan (1.5 and 2.0% (w/w)) showed a significantly greater gel strength when pectin was present in the formulation. The in vitro release of paracetamol from gels containing 1.5% (w/w) xyloglucan, and 1.5 or 2.0% (w/w) xyloglucan/0.75% (w/w) pectin was diffusion-controlled. Measurement of plasma levels of paracetamol after oral administration to rats of a solution containing 1.5% (w/w) xyloglucan and 0.75% (w/w) pectin showed that a more sustained release and higher drug bioavailability was achieved from the gels formed by the in situ gelation of this formulation compared to that of a 1.5% (w/w) xyloglucan solution; 0.75% (w/w) solutions of pectin did not form gels under these conditions. Visual observation of the contents of the rat stomach at intervals after oral administration showed that the inclusion of pectin in the xyloglucan solutions was effective in reducing gel erosion, so sustaining drug release.

In situ gelling pectin formulations for oral drug delivery at high gastric pH.

The aim of the study was to compare the gelation and drug release characteristics of formulations of pectin with high (31%) and low (9%) degrees of methoxylation over a wide pH range (pH 1.2-5.0). Dilute solutions of pectin (1.5%, w/v) containing complexed calcium ions formed gels in vitro at low pH (pH<2.5) as a consequence of cross-linking of the galacturonic chains by calcium ions released from the complex, but the efficiency of gelation was significantly reduced with increase of pH because of incomplete release of complexed Ca(++). Gelation of formulations of pectin with a degree of esterification of 9% (DE9) was observed over the pH range 2.5-5.0 in the presence of 1.6mM Ca(++), but was incomplete in formulations of pectin with a degree of esterification of 31% (DE31). A sustained release of ambroxol was observed following oral administration of pectin DE9 formulations to gastric-acidity controlled rabbits at pH 5.5-5.7 and visual observation of the stomach contents of these rabbits confirmed in situ gelation of these formulations. There was no evidence of in situ gelation of pectin DE31 formulations under these conditions and a rapid initial drug release was observed. Differences in gelling characteristics in this pH range were attributed to the greater susceptibility of low methoxylated pectin to cross-linking by di- and tri-valent ions present in the gastric juice. It is concluded that formulations of pectin with a low degree of esterification have potential application as in situ gelling vehicles for the sustained delivery of drugs following oral administration under conditions of high gastric pH.

The influence of gastric acidity and taste masking agent on in situ gelling pectin formulations for oral sustained delivery of acetaminophen.

Dilute solutions of pectin containing complexed calcium ions form gels when these ions are released in the acidic environment of the stomach. The aim of this study was to examine the influence of a variation of gastric pH and the addition of a taste masking agent on the gelation of the pectin solutions and on the in vitro and in vivo release of acetaminophen from the gels. Increase of pH above 2.5 and addition of 10% (w/v) D-sorbitol significantly affected the ability of 1.5% (w/v) pectin solutions to form coherent gels in vitro. Gelation of sorbitol-free formulations was observed at pH 1.2 and in vitro release of acetaminophen from the gels followed diffusion-controlled kinetics; in vitro gelation of these formulations, however, was incomplete at pH 3.0 resulting in poor sustained release characteristics. Inclusion of 10% (w/v) D-sorbitol in the formulations inhibited the in vitro gelation of the 1.5% (w/v) pectin sols and poor sustained release properties were noted from these formulations even at pH 1.2. The bioavailability of acetaminophen from gels formed in the stomach of gastric-acidity controlled rabbits following oral administration of the liquid formulations was not, however, significantly affected either by the inclusion of 10% (w/v) D-sorbitol or increase of pH to 3.6. Visual observation showed in situ gelation of 1.5% (w/v) pectin formulations containing D-sorbitol at pH 4.3 suggesting that normal variations of gastric acidity in the fasting state will have no effect on the bioavailability of acetaminophen when delivered using these formulations.

The influence of variation of gastric pH on the gelation and release characteristics of in situ gelling pectin formulations.

The aim of this study was to examine the influence of variation of gastric pH over the range 1-3 on the gelation of liquid formulations of pectin and on the in vitro and in vivo release of paracetamol and ambroxol from the resultant gels. The formulations were dilute solutions of pectin containing complexed calcium ions that form gels when these ions are released in the acidic environment of the stomach. Gels suitable as vehicles for sustained delivery of these drugs were formed in vitro at pH<3 from pectin solutions of concentrations 1.0-2.0% (w/v). Very weak gels were formed at pH 3.0 resulting in poor sustained release characteristics compared with those at pH 1.2; no significant in vitro gelation was observed at pH 3.5. The bioavailabilities of paracetamol and ambroxol from gels formed in the stomach following oral administration of the liquid formulations were investigated using gastric-acidity controlled rabbits. Visual observations showed in situ gelation of 1.5% (w/v) pectin formulations under conditions of both high (pH 1.0-1.6) and low gastric acidity (pH 3.3-3.6). The bioavailabilities of these drugs were not significantly different when released from gels formed at the two pH limits suggesting that normal variations of gastric acidity in the fasting state will have no effect on the bioavailability of these drugs when delivered using this vehicle.

Oral sustained delivery of theophylline and cimetidine from in situ gelling pectin formulations in rabbits.

The aim of this study was to evaluate the potential of an in situ gelling pectin formulation as a vehicle for the oral sustained delivery of theophylline and cimetidine. In vitro studies demonstrated diffusion-controlled release of theophylline from 1, 1.5, and 2% w/v pectin gels. Release of this drug from 1.5% w/v pectin gels formed in situ in rabbit stomach was sustained over a period of 12 hours giving a theophylline bioavailability some seven fold higher than when administered from a commercial syrup. In contrast, interactions between cimetidine and pectin led to weak gelation of the pectin sols that prevented any meaningful determination of in vitro release characteristics. Similarly, in vivo release profiles from pectin formulations containing cimetidine were similar to that from a solution of this drug in buffer, indicative of weak gelation. Examination of the content of the rabbit stomach 5 hours after administration of 1.5% w/v pectin sols containing drug confirmed gel formation, but gels containing cimetidine were noticeably softer than those containing theophylline.

The effect of taste masking agents on in situ gelling pectin formulations for oral sustained delivery of paracetamol and ambroxol.

The aim of this study was to examine the influence of polyhydric alcohols (taste masking agents) on the rheological properties of in situ gelling pectin formulations and on the in vitro and in vivo release of paracetamol and ambroxol from these formulations. Gelation of orally administered pectin solutions containing calcium in complexed form occurred on release of calcium in the acidic environment of the stomach. Inclusion of 10% (w/v) sorbitol in 2% (w/v) pectin sols reduced the viscosity and ensured Newtonian flow properties. Xylitol and mannitol in similar concentrations were less effective in reducing viscosity; sucrose increased viscosity and caused non-Newtonian flow. The in vitro release of paracetamol from 2% (w/v) pectin gels formulated with 10% (w/v) of sorbitol, erythritol, xylitol or mannitol, and of ambroxol from 2% (w/v) pectin gels containing 10% (w/v) sorbitol, followed diffusion-controlled kinetics. Pectin gels (2%, w/v) containing sorbitol (10%, w/v) sustained the release of paracetamol in the rat stomach and bioavailabilities of approximately 90% of those from an orally administered paracetamol syrup were achieved. Sustained release of ambroxol from in situ gelling formulations was achieved with pectin concentrations of 1.5 and 1% (w/v) and a sorbitol concentration of 10% (w/v).

In situ gelling pectin formulations for oral sustained delivery of paracetamol.

The purpose of this study was to evaluate the potential of a pectin formulation with in situ gelling properties for the oral sustained delivery of paracetamol (acetaminophen). The formulations consisted of dilute aqueous solutions (1% to 2% w/v) of low methoxy pectin containing calcium ions in complexed form, which on release in the acidic environment of the stomach caused gelation of the pectin. In vitro studies demonstrated diffusion-controlled release of paracetamol from the gels over a period of 6 h. A bioavailability of approximately 96% of that of a paracetamol solution could be achieved from gels containing an identical dose of drug formed in situ in the stomachs of rats, with appreciably lower peak plasma levels and a sustained release of drug over a period of at least 6 h.

Oral sustained delivery of ambroxol from in situ-gelling pectin formulations.

Gels formed in situ following oral administration of dilute aqueous solutions of pectin (1.0 and 1.5%, w/v) to rats were evaluated as vehicles for the sustained release of the expectorant drug ambroxol hydrochloride. The solutions contained calcium ions in complexed form, which on release in the acidic environment of the stomach caused gelation of the pectin. In vitro studies demonstrated diffusion-controlled release of ambroxol from the gels over a period of 6 h. A bioavailability of ambroxol of approximately 64% of that of a commercially available formulation could be achieved from gels containing an identical dose of ambroxol formed in situ in the stomachs of rats, with appreciably lower peak plasma levels and a sustained release of drug over a period of at least 6 h. The influence of added sorbitol (17%, w/v) on the rheological and drug release properties of the formulations has been examined.