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Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and “first pass“ metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract.

The aim of this research was to investigate the effect of the lipid component in self-emulsifying drug delivery systems on the oral absorption of major cannabinoids Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD). The investigated lipids were either long chain triglycerides (LCT) or medium chain triglycerides (MCT) with different composition, fatty acid chain length, degree of saturation and their absorption pathway to the systemic circulation. Formulations were developed with the purpose of creating thermodynamically stable oil-in-water nano emulsions/suspensions with particle size of 50 nm or less which carry the lipophilic drug and increase water solubility. Following a methodic screening of suitable excipients in-vitro, leading formulations based on sesame oil or MIGLYOL® 812N (Type I LCT/MCT SNEDDS) and cocoa butter or tricaprin (Type II LCT/MCT SNEDDS) were investigated in the freely moving rat model. Results in rat model demonstrated that the effect of each type of lipid on bioavailability of cannabinoids is not straightforwardly anticipated. The differences in the effect of LCT and MCT on absorption was not substantial for Type I formulations, however, more prominent for Type II formulations. This unpredictable behavior in-vivo demonstrates the importance of investigating each vehicle pre-clinically, following the in-vitro development.

A high-fat meal induces transient hyperlipidemia characterized by elevated triglyceride-rich lipoproteins (TRL) which are composed mainly of chylomicrons. The purpose of this work was to investigate the effect of this transient hyperlipidemia on the pharmacodynamics of lipophilic drugs, using DDT as a model compound since it binds extensively to TRL and has a distinct neurotoxic effect. The postprandial hyperlipidemia in rats was induced by oral administration of peanut oil and was monitored by measurement of plasma triglyceride levels. The control group received water instead of oil. The rats received a continuous intravenous infusion of DDT (10 mg/h) until onset of a predefined pharmacodynamic endpoint (facial muscle tremor). Plasma and brain samples were then obtained and assayed for DDT. Rats with postprandial hyperlipidemia required higher dose of DDT to induce onset of facial muscle tremor. At the pharmacodynamic endpoint, oil treated rats had significantly higher concentrations of DDT in plasma and in the chylomicron fraction, but DDT brain concentrations were the same in both groups. In conclusion, a high-fat meal induces postprandial hyperlipidemia that may significantly alter the pharmacological profile of lipophilic compounds that bind to TRL. This is due to alteration of the distribution characteristics of the lipophilic compound through its association with postprandial lipoproteins. However, this pharmacokinetic phenomenon did not affect the concentration-effect relationship at the site of action in the brain.

We have recently discovered that peptides are absorbed biologically intact from the rat uterus. The purpose of this investigation was to assess whether EPO, a large polypeptide hormone (34.5 kDa), can be absorbed from the uterus into the systemic blood circulation in a biologically active form, and to compare the biological effects of continuous transendometrial (TE) administration of EPO with those of the pulsatile mode. Sprague-Dawley rats with gentamicin-induced anemia were treated with recombinant human erythropoietin (r-HuEPO) 200 U/kg per day for 5 days as follows: (1) the daily dose was instilled as a bolus through an indwelling cannula in the uterus; (2) the daily dose was continuously delivered into the uterus at a constant rate of 2 U /h by mini-osmotic pump connected to a similar cannula; (3) the third group received the daily r-HuEPO dose through the jugular vein; and (4) a control group treated with normal saline solution instilled in the uterus (as in group 1). The hematological parameters were measured for 53 days following initiation of r-HuEPO treatment. It was found that the biological effects following bolus daily transendometrial (TE) administration of EPO, expressed by red blood cell count and hematocrit levels, were equipotent to i.v. injection. On the other hand, the biological response following continuous TE EPO administration was significantly better than that observed following pulsatile administration. It is concluded that r-HuEPO is absorbed from the uterus in its bioactive form, with no deleterious effects on the uterine tissue. Slow release of EPO from a TE device may induce a beneficial biological response in comparison to pulsatile delivery.

Controlled release gastroretentive dosage forms (CR-GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. CR-GRDF provide a means to utilize all the pharmacokinetic (PK) and pharmacodynamic (PD) advantages of controlled release dosage forms for such drugs. Thus, CR-GRDF may improve therapy with clinically used medications, as well as enable oral administration of drugs, or drug candidates, that hitherto had to be infused parenterally. This manuscript discusses the complexity of the PK and PD factors that influence the treatment benefits of CR-GRDF and summarizes the results of our recent in vivo investigations in animal models (rats and dogs) and in human subjects. We found that a CR-GRDF formulation was superior to the other modes of administration for levodopa and riboflavin, but not for metformin. The PK and PD rationales of GRDFs for the studied drugs are presented and discussed. We conclude that due to the complexity of the PK and PD factors for a certain drug, the rationale for continuous administration obtained by CR-GRDF should be assessed and established in vivo.

We investigated the influence of mode of administration on the pharmacokinetics of a clinically used bisphosphonate, pamidronate, and of suberoylbisphosphonate (SuBP), a novel bisacylphosphonate of the P–CO–(C)n–CO–P type, in rats. Serum drug levels and tissue disposition were determined following administration of the drugs by different modes: intravenous bolus (iso-osmotic and hypo-osmotic solutions), continuous intravenous infusion, and peroral administration. Results of the study indicate that the disposition of the bisphosphonates in soft tissue (liver, kidney and spleen) was dependent on route and rate of drug administration, and on the osmoticity of the vehicle. Consequently, main pharmacokinetic parameters (AUC, CL, and Vss) were influenced by the mode of drug administration, precluding accurate determination of bioavailability from AUC values. On the other hand, bone and urine bisphosphonate accumulation were considerably less dependent on mode of administration, and, therefore, are recommended for bioavailability calculation. © 2001 Elsevier Science B.V. All rights reserved.

The kinetics of release from a population of microparticles is determined by the distribution of a small number of parameters governing the release function in a heterogeneous population. A general model for treatment of the distribution is developed for any release pattern common to a whole population, which is shown to lead to a variety of different cumulative release equations, including those hitherto considered to govern the release mechanism from microcapsules. Thus, the main case, that of constant release rate from individuals differing in rate constant, is shown to yield, according to the statistical distribution of the parameters, ensemble kinetics following first-order, square-root of time (Higuchi's equation), cube-root law (Hixson-Crowell) or a combination of initial zero-order followed by square-root of time relationships, all of which have been used to describe experimental systems studied. It is demonstrated that the cumulative release kinetics observed in a multiparticle system, being a function of the statistical distribution of parameters, does not characterize the basic release mechanism, which can only be determined directly from studies on individuals. The treatment also shows that in the case of first-order release by individuals, the ensembles cannot also observe first-order kinetics, except in the rare case of homogeneity of the determining parameters in the population.

For assessing theories underlying release kinetics of contents from ensembles of microparticles in multiparticle dispersions, population release studies are incapable of revealing the operative physicochemical mechanism, in spite of attempts by many authors to interpret such cumulative data. The present study pioneers techniques for determining release kinetics from single microparticles, using microcapsules as model systems with microconductimetric or spectrophotometric measurement of contents released into the external medium. In four systems giving overall first-order release from populations, the individuals all released their contents at constant rates almost to total payload. A statistical model relating the sum of individual release to cumulative release was applied to the data. It was based on the distribution of two fundamental parameters of the individuals, m ∞ the payload and t ∞ the time to complete release. Statistical analysis of the experimental data validated the proposed relation in the four systems. The conditions required to obtain first-order cumulative kinetics from summated single constant rate data are either: (1) gamma-distribution with shape parameter = 2 of t ∞ and independence of m ∞ and t ∞ ; or (2) exponential distribution of t ∞ and correlation betw m ∞ and t ∞ . Cumulative kinetics and rate constants based on an approximation to a standard release equation are useful for characterization of batch release properties (e.g. in checking repeatability, effects of production variables, sustained release character under controlled conditions) but do not reveal the underlying release mechanism or the actual distribution of parameters, which require studies on individuals. Cumulative kinetics may in fact be altered if the distribution profile of the population undergoes accidental or pre-determined change.