A New Class of Safe Oligosaccharide Polymer Therapy To Modify the Mucus Barrier of Chronic Respiratory Disease.

The host- and bacteria-derived extracellular polysaccharide coating of the lung is a considerable challenge in chronic respiratory disease and is a powerful barrier to effective drug delivery. A low molecular weight 12-15-mer alginate oligosaccharide (OligoG CF-5/20), derived from plant biopolymers, was shown to modulate the polyanionic components of this coating. Molecular modeling and Fourier transform infrared spectroscopy demonstrated binding between OligoG CF-5/20 and respiratory mucins. Ex vivo studies showed binding induced alterations in mucin surface charge and porosity of the three-dimensional mucin networks in cystic fibrosis (CF) sputum. Human studies showed that OligoG CF-5/20 is safe for inhalation in CF patients with effective lung deposition and modifies the viscoelasticity of CF-sputum. OligoG CF-5/20 is the first inhaled polymer therapy, represents a novel mechanism of action and therapeutic approach for the treatment of chronic respiratory disease, and is currently in Phase IIb clinical trials for the treatment of CF.

Development and mechanical characterization of solvent-cast polymeric films as potential drug delivery systems to mucosal surfaces.

Solvent-cast films from three polymers, carboxymethylcellulose (CMC), sodium alginate (SA), and xanthan gum, were prepared by drying the polymeric gels in air. Three methods, (a) passive hydration, (b) vortex hydration with heating, and (c) cold hydration, were investigated to determine the most effective means of preparing gels for each of the three polymers. Different drying conditions [relative humidity - RH (6-52%) and temperature (3-45 degrees C)] were investigated to determine the effect of drying rate on the films prepared by drying the polymeric gels. The tensile properties of the CMC films were determined by stretching dumbbell-shaped films to breaking point, using a Texture Analyser. Glycerol was used as a plasticizer, and its effects on the drying rate, physical appearance, and tensile properties of the resulting films were investigated. Vortex hydration with heating was the method of choice for preparing gels of SA and CMC, and cold hydration for xanthan gels. Drying rates increased with low glycerol content, high temperature, and low relative humidity. The residual water content of the films increased with increasing glycerol content and high relative humidity and decreased at higher temperatures. Generally, temperature affected the drying rate to a greater extent than relative humidity. Glycerol significantly affected the toughness (increased) and rigidity (decreased) of CMC films. CMC films prepared at 45 degrees C and 6% RH produced suitable films at the fastest rate while films containing equal quantities of glycerol and CMC possessed an ideal balance between flexibility and rigidity.

In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog.

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo gamma-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly (p>0.05) from the in-vitro lag time. Additionally, no significant difference (p<0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2=0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC(0-6 dis), K(el), Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.

Nasal residence of insulin containing lyophilised nasal insert formulations, using gamma scintigraphy.

Bioadhesive dosage forms are a potential method for overcoming rapid mucociliary transport in the nose. A lyophilised nasal insert formulation previously investigated in sheep demonstrated prolonged absorption of nicotine hydrogen tartrate suggestive of extended nasal residence, and increased bioavailability. The current study was performed to quantify nasal residence of the formulations using gamma scintigraphy, and to investigate the absorption of a larger molecule, namely insulin. A four-way crossover study was conducted in six healthy male volunteers, comparing a conventional nasal spray solution with three lyophilised nasal insert formulations (1-3% hydroxypropylmethylcellulose (HPMC)). The conventional nasal spray deposited in the posterior nasal cavity in only one instance, with a rapid clearance half-life of 9.2 min. The nasal insert formulations did not enhance nasal absorption of insulin, however an extended nasal residence time of 4-5 h was observed for the 2% HPMC formulation. The 1% HPMC insert initially showed good spreading behaviour; however, clearance was faster than for the 2% formulation. The 3% HPMC nasal insert showed no spreading, and was usually cleared intact from the nasal cavity within 90 min. In conclusion, the 2% HPMC lyophilised insert formulation achieved extended nasal residence, demonstrating an optimum combination of rapid adhesion without over hydration.

The use of simple dynamic mucosal models and confocal microscopy for the evaluation of lyophilised nasal formulations.

A range of methods is reported in the literature for assessing hydration and adhesion parameters in the performance of nasal bioadhesive formulations; however, these tests do not always represent the dynamic conditions in the nasal cavity. Lyophilised formulations intended for nasal administration were evaluated using in-vitro tests designed in an attempt to mimic relevant processes in the nasal cavity, and intended to discriminate between different formulations. Initial investigative studies using scanning electron microscopy revealed that the lyophilisate had a highly porous internal structure, expected to provide an ideal porous pathway for re-hydration. Vapour sorption analysis demonstrated substantial weight gain of the lyophilisates on exposure to 95% relative humidity, ranging from 38% to 66%. Agar was used as a synthetic mucosal model designed to provide a standardised quantity of water available for rehydration of the formulations in in-vitro tests. A dynamic adhesion test and a texture analyser sliding test were designed to quantify different aspects of the spreading and adhesion of the hydrating formulations on the synthetic mucosal surface. Examination of the lyophilised formulations using confocal microscopy allowed visualisation and quantification of the initial rate of water ingress into the lyophilisates, which was found to consist of an initial rapid phase, followed by a slower steady-state phase. The results demonstrated that the use of a combination of methods representing the dynamic conditions of the nasal cavity is advisable in order to evaluate a formulation fully and to avoid misleading conclusions.

In vivo evaluation of nicotine lyophilised nasal insert in sheep.

The nasal route offers an attractive means of delivering a drug directly to the systemic circulation and avoiding hepatic first-pass metabolism, although rapid mucociliary clearance can be detrimental to nasal absorption. The in vitro and in vivo characteristics of a nasal insert formulation prepared by lyophilisation of a viscous HPMC gel solution designed to overcome this problem were studied. In vitro release of nicotine from the lyophilised insert was compared with powder and spray formulations. Stability and characterisation studies were carried out using dynamic vapour sorption, scanning electron microscopy and HPLC analysis. Nicotine formulations were administered to eight wether sheep in a randomised four-way cross-over study, and plasma nicotine assessed comparing the nasal insert formulation with conventional nasal powder, nasal spray and IV doses. In vitro release studies demonstrated prolonged nicotine release from the nasal insert formulation compared to a powder and liquid. In vivo plasma profiles appeared to show prolonged plasma nicotine levels compared to the conventional formulations, although T(max), C(max) and AUC parameters for the insert were not significantly different due to high variability in the pharmacokinetic data. In conclusion, the nasal insert displayed a promising prolonged plasma profile, which must be investigated further to provide statistical significance to prove the effect.

Investigating the coating-dependent release mechanism of a pulsatile capsule using NMR microscopy.

Chronopharmaceutical capsules, ethylcellulose-coated to prevent water ingress, exhibited clearly different release characteristics when coated by organic or aqueous processes. Organic-coated capsules produced a delayed pulse release, whereas aqueous-coated capsules exhibited less delayed and more erratic release behaviour. Nuclear magnetic resonance microscopy was used to elucidate the internal mechanisms underlying this behaviour by studying the routes of internal water transport and the timescale and sequence of events leading to the pulse. Images showed that the seal between the shell and the tablet plug is a key route of water penetration in these dosage forms. There is evidence for a more efficient seal in the organic-coated capsule, and although some hydration of the contents was evident, erosion of the tablet plug is most probably the controlling factor in timed release. The premature failure of the aqueous-coated capsule appears to be a result of rapid influx of water between plug and capsule with hydration of the low substituted hydroxypropylcellulose expulsion agent. As a result of this, the tablet plug remains intact, but appears unable to be ejected. The resulting significant pressure build-up causes premature release by distortion and splitting of the capsule shell. These events may be aided by a weakening of the aqueous-coated gelatin shell by hydration from the inside, and at the mouth of the capsule where previous electron microscope studies have shown incomplete coating of the inside by the aqueous process.

The effect of wet granulation on the erosion behaviour of an HPMC-lactose tablet, used as a rate-controlling component in a pulsatile drug delivery capsule formulation.

The purpose of this study was to investigate the variability in the performance of a pulsatile capsule delivery system induced by wet granulation of an erodible HPMC tablet, used to seal the contents within an insoluble capsule body. Erodible tablets containing HPMC and lactose were prepared by direct compression (DC) and wet granulation (WG) techniques and used to seal the model drug propranolol inside an insoluble capsule body. Dissolution testing of capsules was performed. Physical characterisation of the tablets and powder blends used to form the tablets was undertaken using a range of experimental techniques. The wet granulations were also examined using the novel technique of microwave dielectric analysis (MDA). WG tablets eroded slower and produced longer lag-times than those prepared by DC, the greatest difference was observed with low concentrations of HPMC. No anomalous physical characteristics were detected with either the tablets or powder blends. MDA indicated water-dipole relaxation times of 2.9, 5.4 and 7.7x10(-8)ms for 15, 24 and 30% HPMC concentrations, respectively, confirming that less free water was available for chain disentanglement at high concentrations. In conclusion, at low HPMC concentrations water mobility is at its greatest during the granulation process, such formulations are therefore more sensitive to processing techniques. Microwave dielectric analysis can be used to predict the degree of polymer spreading in an aqueous system, by determination of the water-dipole relaxation time.

Evaluation of Pulsincap to provide regional delivery of dofetilide to the human GI tract.

Pulsincap formulations designed to deliver a dose of drug following a 5-h delay were prepared to evaluate the capability of the formulation to deliver dofetilide to the lower gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug absorption to be determined as a function of GI tract site of release. Dofetilide is a well-absorbed drug, but showed a reduction in observed bioavailability when delivered from the Pulsincap formulations, particularly at more distal GI tract sites. Dispersion of the drug from the soluble excipient used in this prototype formulation relies on a passive diffusion mechanism and the relevance of this factor to the reduced extent and consistency of absorption from the colon is discussed. In these studies the effects of the degree of dispersion versus the site of dispersion could not be ascertained; nevertheless the scintigraphic analysis demonstrated good in vitro-in vivo correlation for time of release from Pulsincap preparations. The combination of scintigraphic and pharmacokinetic analysis permits identification of the site of drug release from the dosage form and pharmacokinetic parameters to be studied in man in a non-invasive manner.

Correlation between in vitro and in vivo erosion behaviour of erodible tablets using gamma scintigraphy.

In vitro and in vivo erosion behaviour of erodible tablets consisting of glyceryl behenate and low-substituted hydroxypropylcellulose manufactured using three different methods: direct compression (DC), melt granulation (MG) and direct solidification (DS) was investigated. In vitro erosion behaviour was studied using gravimetric and scintigraphic methods. For scintigraphic investigations, the radiolabel was adsorbed onto activated charcoal and incorporated into tablets at a concentration that did not affect the erosion profile. A clinical study was carried out in six healthy volunteers using gamma scintigraphy. Tablet erosion was affected by the preparation method and was found to decrease in the order of preparation method, DC>MG>DS tablets. The mean in vivo onset time for all tablets (DC: 6.7±3.8 min, MG: 18.3±8.1 min, DS: 67±18.9 min) did not differ significantly from in vitro onset time (DC: 5.3±1 min, MG: 16.8±3.9 min, DS: 61.8±4.7 min). The mean in vivo completion times were found to be 36.6±9.7 (DC tablets), 70±18.3 min (MG tablets) and 192.5±39.9 min (DS tablets). Among the three different erodible tablets, MG tablets showed the highest correlation between in vitro and in vivo mean erosion profile and suggested a potential platform to deliver controlled release of water-insoluble compounds.

In-vitro and in-vivo erosion profiles of hydroxypropylmethylcellulose (HPMC) matrix tablets.

The purpose of this study was to evaluate and compare the in-vitro and in-vivo erosion profiles of two tablet formulations primarily consisting of hydroxypropylmethylcellulose (HPMC) and lactose. HPMC was used at concentrations below and above the reported values for polymer percolation threshold in controlled release matrix formulations: 20 and 40% (w/w) HPMC. In-vitro erosion behaviour was studied using traditional gravimetric and scintigraphic methods, with radiolabelled charcoal used as a marker to quantify erosion profiles in scintigraphic studies. Six healthy male subjects participated in a randomised crossover scintigraphic erosion study. Both in-vitro and in-vivo erosion profiles determined using the gravimetric and/or scintigraphic method for matrix tablets were dependent upon the concentration of HPMC, and erosion was faster for tablets containing 20% (w/w) HPMC than those containing 40% (w/w) HPMC. Good correlation was found between in-vitro gravimetric and scintigraphic erosion profiles for both tablets. Tablets containing 40% (w/w) HPMC (polymer level above percolation threshold) demonstrated robust in-vivo performance and showed stronger correlation with in-vitro erosion profiles. The study demonstrated that a matrix formulation with a lower concentration of HPMC and higher lactose concentration is more likely to perform poorly in the in-vivo environment.

Assessing gastrointestinal motility and disintegration profiles of magnetic tablets by a novel magnetic imaging device and gamma scintigraphy.

PURPOSE: To validate Magnetic Moment Imaging (MMI) for the investigation of gastrointestinal transit and disintegration of solid dosage forms and to correlate the MMI findings with the corresponding gamma scintigraphic data. MATERIALS AND METHODS: Three magnetic tablets (MTs) were investigated using in vitro and in vivo tests. The clinical study was a four-way, crossover study with the following arms: (a) immediate-release tablets administered in fasted state; (b) immediate-release tablets administered after 400mL of Clinutren ISO; (c) enteric-coated tablets administered in the fasted state; and (d) non-disintegrating tablets studied in the lightly fed state (100mL of Clinutren ISO). RESULTS: In both the in vitro and in vivo studies, tablets were detected successfully by MMI and scintigraphy. There was a good correlation between gastric residence times and positional data (in the x, y and y, z-axes). In addition, MMI revealed early swelling behaviour of the tablet matrix. There was excellent agreement for the disintegration times of MT(A) in the fasted arm (scintigraphy 12.0+/-4.4min, MMI 11.8+/-4.4min). In the MT(A)-fed arm, onset times determined by scintigraphy were delayed in three subjects when compared to the corresponding MMI results. Delayed disintegration was observed with MT(A) administered after food (p<0.01) in both the techniques. CONCLUSION: The MMI device is a reliable imaging tool for tracking the transit and disintegration of a magnetic tablet through the gastrointestinal tract.

Characterisation of freeze-dried wafers and solvent evaporated films as potential drug delivery systems to mucosal surfaces.

Freeze-dried (lyophilised) wafers and solvent cast films from sodium alginate (ALG) and sodium carboxymethylcellulose (CMC) have been developed as potential drug delivery systems for mucosal surfaces including wounds. The wafers (ALG, CMC) and films (CMC) were prepared by freeze-drying and drying in air (solvent evaporation) respectively, aqueous gels of the polymers containing paracetamol as a model drug. Microscopic architecture was examined using scanning electron microscopy, hydration characteristics with confocal laser scanning microscopy and dynamic vapour sorption. Texture analysis was employed to investigate mechanical characteristics of the wafers during compression. Differential scanning calorimetry was used to investigate polymorphic changes of paracetamol occurring during formulation of the wafers and films. The porous freeze-dried wafers exhibited higher drug loading and water absorption capacity than the corresponding solvent evaporated films. Moisture absorption, ease of hydration and mechanical behaviour were affected by the polymer and drug concentration. Two polymorphs of paracetamol were observed in the wafers and films, due to partial conversion of the original monoclinic to the orthorhombic polymorph during the formulation process. The results showed the potential of employing the freeze-dried wafers and solvent evaporated films in diverse mucosal applications due to their ease of hydration and based on different physical mechanical properties exhibited by both type of formulations.

A pharmacoscintigraphic study of three time-delayed capsule formulations in healthy male volunteers.

Three time-delayed capsule (TDC) formulations were investigated in a pharmacoscintigraphic study, using a three-way crossover design in eight healthy male volunteers. Additionally, the pulsed release of a TDC was investigated with time-lapse photography, using a nondisintegrating riboflavin tablet. The photographic study indicated how the release characteristics of the TDC relied on the erosion of a tablet containing hypromellose (HPMC). Each TDC was duel radio labelled with indium-111 and technetium-99 m DTPA complexes, to observe drug release scintigraphically (theophylline was a marker compound). Three formulations, having in vitro dissolution release times of 1.8, 2.9 or 4.0 h were shown to compare favourably with mean in vivo scintigraphic release times of 2.7, 3.0 and 4.0 h for each formulation containing 20, 24 or 35% (w/w) HPMC concentrations respectively. An increase in HPMC concentration was associated with a delayed technetium release time, and followed the same rank order as the in vitro dissolution study. Observed radiolabel dispersion always occurred in the small intestine. In conclusion, the study established that the TDC performs and demonstrates an in vitro-in vivo correlation. Additionally, time and site of release were accurately visualized by gamma scintigraphy, and confirmed with determination of theophylline absorption.

In vivo performance of an oral MR matrix tablet formulation in the beagle dog in the fed and fasted state: assessment of mechanical weakness.

PURPOSE: To evaluate the behaviour of an oral matrix modified release formulation in the canine gastrointestinal tract, and establish if a mechanical weakness previously observed in clinical studies would have been identified in the dog model. MATERIALS AND METHODS: In vitro release profiles were obtained for two modified release matrix tablets containing UK-294,315, designed to release over either 6 (formulation A) or 18 (formulation B) hours. Tablets were labelled with (153)samarium and in vivo pharmacoscintigraphy studies were performed in four beagle dogs in the fasted state for both formulations, and following ingestion of an FDA high fat meal for formulation B. RESULTS: The matrix tablet formulations displayed significantly different in vitro release profiles (F (2) < 50), with time to 80% release for formulation A and B of 406 and 987 min respectively. Complete in vivo disintegration occurred at 339 +/- 181 and 229 +/- 171 for formulation A and B respectively in the fasted state, and at 207 +/- 154 min for formulation B in the fed state, in disagreement with in vitro release. CONCLUSION: The fed/fasted dog model would have predicted a lack of physical robustness in the matrix tablet formulation B, however it would not have predicted the clear fed/fasted effects on performance observed previously in man.

Wound healing dressings and drug delivery systems: a review.

The variety of wound types has resulted in a wide range of wound dressings with new products frequently introduced to target different aspects of the wound healing process. The ideal dressing should achieve rapid healing at reasonable cost with minimal inconvenience to the patient. This article offers a review of the common wound management dressings and emerging technologies for achieving improved wound healing. It also reviews many of the dressings and novel polymers used for the delivery of drugs to acute, chronic and other types of wound. These include hydrocolloids, alginates, hydrogels, polyurethane, collagen, chitosan, pectin and hyaluronic acid. There is also a brief section on the use of biological polymers as tissue engineered scaffolds and skin grafts. Pharmacological agents such as antibiotics, vitamins, minerals, growth factors and other wound healing accelerators that take active part in the healing process are discussed. Direct delivery of these agents to the wound site is desirable, particularly when systemic delivery could cause organ damage due to toxicological concerns associated with the preferred agents. This review concerns the requirement for formulations with improved properties for effective and accurate delivery of the required therapeutic agents. General formulation approaches towards achieving optimum physical properties and controlled delivery characteristics for an active wound healing dosage form are also considered briefly.

Evaluation of the clearance of a sublingual buprenorphine spray in the beagle dog using gamma scintigraphy.

PURPOSE: The aim of this study was to evaluate clearance from the buccal cavity and pharmacokinetic profiles of a sublingual spray formulation in the dog, to assist in interpretation of future pharmacokinetic studies. METHODS: Radiolabelled buprenorphine in a spray formulation (400 microg/100 microl in 30% ethanol) was administered sublingually to four beagle dogs, and the residence in the oral cavity was determined using gamma scintigraphy. Pharmacokinetic sampling was performed to facilitate correlation of location of dose with significant pharmacokinetic events. RESULTS: Scintigraphic imaging revealed that clearance of the formulation from the oral cavity was rapid, with a mean T 50% clearance of 0.86 +/- 0.46 min, and T 80% clearance of 2.75 +/- 1.52 min. In comparison, absorption of buprenorphine was relatively slow, with a T max of 0.56 +/- 0.13 h. Good buccal absorption despite short residence time can be explained by lipophilicity of buprenorphine enabling rapid sequestration into the oral mucosa, prior to diffusion and absorption directly into systemic circulation. CONCLUSION: This study demonstrated rapid clearance of a sublingual solution from the canine oral cavity, with T 50% similar to results previously reported in man, providing initial confidence in using a conscious dog model to achieve representative residence times for a sublingual solution.

Erosion characteristics of an erodible tablet incorporated in a time-delayed capsule device.

A time-delayed oral drug delivery device was investigated in which an erodible tablet (ET), sealing the mouth of an insoluble capsule, controlled the lag-time prior to drug release. The time-delayed capsule (TDC) lag-time may be altered by manipulation of the excipients used in the preparation of the ET. Erosion rates and drug release profiles from TDCs were investigated with four different excipient admixtures with lactose: calcium sulphate dihydrate (CSD), dicalcium phosphate (DCP), hydroxypropylmethyl cellulose (HPMC; Methocel K100LV grade) and silicified microcrystalline cellulose (SMCC; Prosolv 90 grade). Additionally, the compressibility of different insoluble coated capsules was tested at different moisture levels to determine their overall integrity and suitability for oral delivery. Erosion rates of CSD, DCP, and SMCC displayed a nonlinear relationship to their concentration, while HPMC indicated rapid first-order erosion followed by zero-order erosion, the onset of which was dependent on the HPMC concentration. Capsule integrity was confirmed to be most suitable for oral delivery when the insoluble ethyl cellulose coat was applied to a hard gelatin capsule using an organic spray coating process. T50% drug release times varied between 245 (+/-33.4) and 393 (+/-40.8) minutes for 8% and 20% DCP, respectively, T50% release times of 91 (+/-22.1) and 167 (+/-34.6) were observed for 8% and 20% CSD; both formulations showed incidence of premature drug release. The SMCC formulations showed high variability due to lamination effects. The HPMC formulations had T50% release times of 69 (+/-13.9), 213 (+/-25.4), and 325 (+/-30.3) minutes for 15%, 24%, and 30% HPMC concentrations respectively, with no premature drug release. In conclusion, HPMC showed the highest reproducibility for a range of time-delayed drug release from the assembled capsule formulation. The method of capsule coating was confirmed to be important by investigation of the overall capsule integrity at elevated humidity levels. The erosion characteristics of ETs containing HPMC may be described by gravimetric loss. The novel time-delayed capsule device presented in this study may be assembled to include an erodible tablet with a known concentration of HPMC. A variety of suitable drugs for targeted chronopharmaceutical therapy can be incorporated into such a device, ultimately improving drug efficacy and patient compliance, and reducing harmful side effects.

Comparison of the rates of disintegration, gastric emptying, and drug absorption following administration of a new and a conventional paracetamol formulation, using gamma scintigraphy.

PURPOSE: To investigate the hypothesis that faster drug absorption from a new paracetamol formulation containing sodium bicarbonate compared to that from a conventional formulation results from a combination of enhanced gastric emptying and disintegration/dissolution. METHODS: Each formulation was administered in both fasted and fed states to 12 healthy volunteers. Gastric emptying and disintegration times were assessed by gamma scintigraphy, and serum paracetamol concentrations were determined by HPLC. RESULTS: The mean time to complete disintegration of the new tablets was faster than that for conventional tablets in both fasted (10.2 min vs. 22.5 min) and fed (14.3 min vs. 46.4 min) states, although this difference was statistically significant in the fed state only (p = 0.0053). Mean gastric emptying times for the new tablets, as measured by t50 and t90, were also faster than those for conventional tablets in both fasted (t50 = 22.4 min vs. 47.5 min, t90 = 30.9 min vs. 64.1 min) and fed (t50 = 76.9 min vs. 106.4 min, t90 = 152.7 min vs. 155.5 min) states, although these differences were not statistically significant. Two subjects showed dramatically retarded gastric emptying of the new tablets in the fasted state: if these atypical data are excluded, the differences in both t50 and t90 in the fasted state are significant (p = 0.0110 and 0.0035, respectively). Rate of paracetamol absorption reflected the gastric emptying profiles as shown by significant correlation of emptying times with partial AUC. CONCLUSIONS: It would seem that a combination of faster disintegration and gastric emptying of the new tablets is responsible for the faster rate of absorption of paracetamol from PA compared to P observed in both this study and in previous studies. The differences in gastric emptying are more pronounced in the fasted state, and the differences in disintegration are more pronounced in the fed state.