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Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06-0.14) mg/L and 0.07 (0.05-0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10-7.26) mg/L and 1.81 (1.20-7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3-162.7) and 21.2 (18.4-109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high., (Copyright © 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Purpose: To compare the relative bioavailability of levetiracetam extended-release tablets (XR) with immediate release tablets (IR) following single and multiple dosing; to assess the food effect and the dose-proportionality of XR from 1000 to 3000mg., Methods: Two panels of 24 healthy subjects were enrolled. Study N01160 was a three-way crossover between IR fasted (single and repeated 500mg b.i.d.), XR fasted (single and repeated 1000mg o.d.) and XR with food (1000mg single dose). Study N01260 was a three-way crossover single dose-proportionality between XR 1000, 2000 and 3000mg., Results: After single dose, levetiracetam XR and IR were bioequivalent with respect to AUC((0-t)), AUC(infinity) and C(max). The median t(max) was delayed from 0.9 to 4h. For the fed/fasted comparison, the confidence intervals around the C(max) and AUC ratios were within the 80-125% limits. At steady-state, the AUC(24h) were also bioequivalent. In the dose-proportionality trial, the AUC and C(max) increased linearly with the dose. Levetiracetam XR was well tolerated., Conclusions: Levetiracetam XR 1000mg o.d. is bioequivalent to levetiracetam IR 500mg b.i.d. There is no food effect, and the absorption of XR is dose-proportional from 1000 to 3000mg.

The mechanism of drug release from push-pull osmotic systems (PPOS) has been investigated by Magnetic Resonance Imaging (MRI) using a new benchtop apparatus. The signal intensity profiles of both PPOS layers were monitored non-invasively over time to characterize the hydration and swelling kinetics. The drug release performance was well-correlated to the hydration kinetics. The results show that (i) hydration and swelling critically depend on the tablet core composition, (ii) high osmotic pressure developed by the push layer may lead to bypassing the drug layer and incomplete drug release and (iii) the hydration of both the drug and the push layers needs to be properly balanced to efficiently deliver the drug. MRI is therefore a powerful tool to get insights on the drug delivery mechanism of push-pull osmotic systems, which enable a more efficient optimization of such formulations.

Mucoadhesive tablets using different mixture of cellulose and polyacrylic derivatives were prepared in order to obtain new formulations containing metronidazole for periodontal disease treatment. All tablets were characterized by swelling studies, ex vivo and in vivo mucoadhesive time, ex vivo mucoadhesion force, in vitro and in vivo release. The best mucoadhesive performance and the best in vitro drug release profile were achieved by using hydroxyethyl cellulose (HEC) and carbomer 940 2:2 ratio. The chosen tablet, containing 20 mg of metronidazole, performed 12 h drug sustained release with buccal concentrations always higher than its MIC.

It was the aim of this study to develop a delivery system providing an improved efficacy of orally administered insulin utilizing a thiolated polymer. 2-Iminothiolane was covalently linked to chitosan. The resulting chitosan-TBA (chitosan-4-thiobutylamidine) conjugate exhibited 453.5+/-64.1 micromol thiol groups per gram polymer. 3.1% of these thiol groups were oxidised. Additionally, the enzyme inhibitors BBI (Bowman-Birk-Inhibitor) and elastatinal were covalently linked to chitosan representing 3.5+/-0.1% and 0.5+/-0.03% of the total weight of the resulting polymer conjugate, respectively. Chitosan-TBA conjugate (5 mg), insulin (2.75 mg), the permeation mediator reduced glutathione (0.75 mg) and the two inhibitor conjugates (in each case 0.75 mg) were compressed to so-called chitosan-TBA-insulin tablets. Control tablets consisted of unmodified chitosan (7.25 mg) and insulin (2.75 mg). Chitosan-TBA-insulin tablets showed a controlled release of insulin over 8 h. In vitro mucoadhesion studies showed that the mucoadhesive/cohesive properties of chitosan were at least 60-fold improved by the immobilisation of thiol groups on the polymer. After oral administration of chitosan-TBA-insulin tablets to non-diabetic conscious rats, the blood glucose level decreased significantly for 24 h corresponding to a pharmacological efficacy of 1.69+/-0.42% (means+/-S.D.; n=6) versus s.c. injection. In contrast, neither control tablets nor insulin given in solution showed a comparable effect. According to these results the combination of chitosan-TBA, chitosan-enzyme-inhibitor conjugates and reduced glutathione seems to represent a promising strategy for the oral application of insulin.

A controlled porosity osmotic pump-based drug delivery system has been described in this study. Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It has a short plasma half life of 5-8 h. Hence, pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate was used as the osmogent. The effect of different ratios of drug:osmogent on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. Different channeling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP), dibutylsebacate (DBS) and polyethyleneglycol 400 (PEG 400). The effect of polymer loading on in-vitro drug release was studied. It was found that drug release rate increased with the amount of osmogent due to the increased water uptake, and hence increased driving force for drug release. This could be retarded by the proper choice of channeling agent in order to achieve the desired zero order release profile. Also the lag time seen with tablets coated using diethylphthalate as channeling agent was reduced by using a hydrophilic plasticizer like polyethyleneglycol 400 in combination with diethylphthalate. This system was found to deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per ICH guidelines at different temperature and humidity conditions.

The effect of ionic and non-ionic excipients and additives as modulators of swelling and erosion kinetics and verapamil HCl release from guar-based matrix tablets was investigated. Tablet dissolution, erosion and water uptake studies were carried out using a modified USP 23 Apparatus 2 method. The kinetics of gel strength and texture development were studied by textural analysis. Near linear drug release over 24 h was obtained from formulations containing water soluble, ionizable sodium chloride and glycine. The contribution of Fickian release to overall drug release was lowest for these formulations and was correlated with greater gel strength and lower water uptake in the early time period. For soluble sugars (lactose and sucrose) the Fickian contribution to overall drug release was large and associated with pronounced curvilinear profiles. Water uptake was greatest for these additives (450% in 6 h). The lowest water uptake and negligible matrix erosion was observed for microcrystalline cellulose. Release from this formulation was predominantly Fickian. It was found that the physico-chemical nature of added excipients significantly influences the release kinetics from guar-based formulations. Ionic, water soluble materials (sodium chloride, glycine) reduce initial hydration of the matrix and thus have the ability to limit the initial rapid diffusion of drug and to sustain near linear release over 24 h.

The objective of the present study was to obtain programmed drug delivery from hard gelatin capsules containing a hydrophilic plug (HPMC or guar gum). The significance of factors such as type of plug (powder or tablet), plug thickness and the formulation of fill material on the release pattern of diltiazem HCl, a model drug, was investigated. The body portion of the hard gelatin capsules was cross-linked by the combined effect of formaldehyde and heat treatment. A linear relationship was observed between weight of HPMC K15M and log % drug released at 4 h from the capsules containing the plug in powder form. In order to accelerate the drug release after a lag time of 4 h, addition of an effervescent blend, NaHCO(3) and citric acid, in the capsules was found to be essential. The plugs of HPMC in tablet form, with or without a water soluble adjuvant (NaCl or lactose) were used for obtaining immediate drug release after the lag time. Sodium chloride did not cause significant influence on drug release whereas lactose favourably affected the drug release. The capsules containing HPMC K15M tablet plug (200 mg) and 35 mg effervescent blend in body portion of the capsule met the selection criteria of less than 10% drug release in 4 h and immediate drug release thereafter. It is further shown that the drug release was also dependant on the type of swellable hydrophilic agent (HPMC or guar gum) and molecular weight of HPMC (K15M or 20 cPs). The results reveal that programmed drug delivery can be obtained from hard gelatin capsules by systemic formulation approach.

The present study investigates the use of a polymer mixture containing Carbopol 974P and drum dried waxy maize starch to obtain prolonged drug release to the anterior eye segment. Two dosage forms with this composition are compared: a hydrated polymer dispersion and a minitablet. A model fluorescent tracer is used to study the ocular release and diffusion from the two dosage forms in humans. To evaluate the prolongation in the cornea/tearfilm compartment, the Apparent Fluorescein TurnOver (%/min) is calculated. The parameters Cmax, tmax, and C9h are used to characterize the pharmacokinetics of Na-fluorescein in the anterior chamber. Furthermore, the swelling behavior of the minitablet is evaluated macroscopically, while the degree of interaction with mucin is characterized by rheological measurements. Calculation of an acceptability score and a slug irritation potential is performed to evaluate user acceptability. In contrast to the hydrated dispersion, the minitablet significantly decreases the Apparent Fluorescein TurnOver (%/min) (P<0.05) and increases the apparent fluorescence in the anterior chamber 9 h after application of the preparation. Rheological data demonstrate the presence of elastic interactions between the polymer and mucin. The dry core of the minitablet becomes fully hydrated after approximately 2 h and is subsequently transformed into a highly concentrated gel. The acceptability of the minitablet is comparable to that of the polymer dispersion. Prolonging the release of Na-fluorescein to the anterior eye segment is only feasible with the dry preparation.

A system for performing NMR imaging experiments on drug delivery devices within a flow-through dissolution apparatus, USP Apparatus 4, has been developed. The system was used to image the physical changes that occur in solid dosage forms during dissolution in the flow-through apparatus. Simultaneous cumulative drug release measurements were also made. The NMR images obtained under these conditions and the drug release data provide a better understanding of the processes involved in the release of drugs from drug delivery systems based on diffusion, dissolution and osmosis mechanisms.