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Apomorphine (APO), a potent treatment for Parkinson's disease, is only administered parenterally either as intermittent injections or as an infusion. This is due to extensive hepatic “first pass” metabolism. Prolonged delivery through buccal mucosa may be potential substitute for parenteral infusions. To investigate this concept of buccal mucosal delivery, permeability ex vivo studies were performed through excised porcine buccal mucosa by utilizing Ussing diffusion chamber. Permeability rates were assessed for APO from simulated saliva medium at pH 7.4 as well as with utilization of different permeability modifying methods. Lowering the pH to 5.9 decreased permeability rate six-fold, while addition of ethanol : propylene glycol solution elevated it four-fold. Addition of nano-scale lipospheres to the donor compartment delayed the accumulation of APO at the receiver side, prolongating the lag-time from one to approx. three hours. These findings were strengthened by results obtained with co-administration of permeability markers (standards) atenolol and metoprolol. Simulation of the obtained permeability rates to in vivo setup in human showed therapeutically relevant plasma levels when using the outcomes of the current study. These findings verify the novel concept of APO prolonged release buccal administration as a noninvasive substitute for parenteral infusions in treating Parkinson's disease.

Lipid-based drug delivery systems have been vastly investigated as a pharmaceutical method to enhance oral absorption of lipophilic drugs. However, these vehicles not only affect drug bioavailability but may also have an impact on gastric emptying, drug disposition, lymphatic absorption and be affected by lipid digestion mechanisms. The work presented here compared the pharmacokinetic (PK) behavior of the non-intoxicating cannabinoid cannabidiol (CBD) in sesame oil

Myeloid differentiation primary response 88 (MyD88) is an intracellular adaptor protein central to the signaling of multiple receptors involved in inflammation. Since innate immune inflammation promotes autoimmunity, MyD88 is an attractive target in autoimmune disease. We previously developed c(MyD 4-4), a novel cyclic peptide competitive inhibitor of MyD88 dimerization that is metabolically stable. Parenteral administration of c(MyD 4-4) reduces disease severity in a mouse model of the human autoimmune disease multiple sclerosis. We now show that N-terminal myristoylation of c(MyD 4-4) enhances the competitive inhibition of MyD88 dimerization in living cells, leading to improved inhibition of the Toll-like receptor and IL-1 receptor signaling. Importantly, myristoylation converts c(MyD 4-4) to an orally bioavailable inhibitor of MyD88. Oral administration of c(MyD 4-4) significantly lowered the inflammatory cytokines secreted by peripheral autoimmune T cells in mice immunized with myelin antigens and ameliorated disease severity in the mouse model of multiple sclerosis. Taken together, we show the conversion of a protein active region to a metabolically stable, selective cyclic peptide that is orally bioavailable.

Contrary to human, porcine mucosa of the inner side of the lip is parakeratinized. Thus, although desirable due to its large surface area, it does not closely resemble human buccal mucosa to be considered a suitable model for systemic drug delivery research. Nevertheless, it can be utilized for comparative screening of topical or systemic delivery of bioactive agents, mostly lipophilic such as cannabinoids.

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 lipophilic phytocannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold increase in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL which resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally.

Nowadays, therapeutic indications for cannabinoids, specifically Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) are widening. However, the oral consumption of the molecules is very limited due to their highly lipophilic nature that leads to poor solubility at the aqueous environment. Additionally, THC and CBD are prone to extensive first pass mechanisms. These absorption obstacles render the molecules with low and variable oral bioavailability. To overcome these limitations we designed and developed the advanced pro-nanolipospheres (PNL) formulation. The PNL delivery system is comprised of a medium chain triglyceride, surfactants, a co-solvent and the unique addition of a natural absorption enhancer: piperine. Piperine was selected due to its distinctive inhibitory properties affecting both Phase I and Phase II metabolism. This constellation self emulsifies into nano particles that entrap the cannabinoids and the piperine in their core and thus improve their solubility while piperine and the other PNL excipients inhibit their intestinal metabolism. Another clear advantage of the formulation is that its composition of materials is approved for human consumption. The safe nature of the excipients enabled their direct evaluation in humans. In order to evaluate the pharmacokinetic profile of the THC-CBD-piperine-PNL formulation, a two-way crossover, single administration clinical study was conducted. The trial comprised of 9 healthy volunteers under fasted conditions. Each subject received a THC-CBD (10.8mg, 10mg respectively) piperine (20mg)-PNL filled capsule and an equivalent dose of the oromucosal spray Sativex® with a washout period in between treatments. Single oral administration of the piperine-PNL formulation resulted in a 3-fold increase in Cmax and a 1.5-fold increase in AUC for THC when compared to Sativex®. For CBD, a 4-fold increase in Cmax and a 2.2-fold increase in AUC was observed. These findings demonstrate the potential this formulation has in serving as a standardized oral cannabinoid formulation. Moreover, the concept of improving oral bioavailability described here, can pave the way for other potential lipophilic active compounds requiring enhancement of their oral bioavailability.

Piperine is an alkaloid naturally found in black pepper with a myriad of pharmacological attributes. Piperine's most far reaching indication is drug absorption enhancment, with supportive data regarding its ability to inhibit first pass effect mechanisms. However, alongside these findings, the role of piperine as an absorption enhancer is undermined with publications stating an apparent effect of a metabolic inducer. The aim of this work is to investigate the effect of repeated administration of piperine in a lipid-based formulation ,on oral absorption of cannabidiol (CBD), compared to acute piperine dosing. The effect of piperine on CBD absorption was determined pre-clinically in the freely moving rat model. Results of this work demonstrated that there was no significant difference in piperine's effect, when given chronically or in a single dose regimen. Both groups resulted in approximate 2.5-fold increase in oral bioavailability of CBD compared to control group without piperine.

Introduction: Sativex® spray is clinically utilized to deliver delta9-tetrahydrocannabinol and cannabidiol to oral mucosa for systemic absorption. We challenge the consensus that the mechanism of absorption following the oro-mucosal application occurs via the buccal tissue. Areas covered: Correctness of the consensus of this absorption pathway arose when reviewing publications regarding the influence fed versus fasting states have on pharmacokinetics of these cannabinoids administered to the oral mucosa. This finding is more suitable for peroral administration, where stomach content affects the absorption profile. We hypothesize that these cannabinoids are ingested and absorbed in the gastrointestinal tract. Expert opinion: Although clinical importance of Sativex® is not disputed, the wide acceptance of its being a successful example of drug delivery through oral mucosa is questionable. Sativex® acts as an example for other drugs delivered to oral mucosa for systemic absorption and unintentionally washed by the saliva flow into the gastrointestinal tract. Delivery of each medicine through oral mucosa should be validated in-vivo to ensure this route to be the predominant one. Revealing the underlying absorption mechanisms would enable predicting the impact of different physiological parameters such as saliva flow and fed/fasting states on the pharmacokinetics of the delivered medication.

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.

Hydrophilic peptides constitute most of the active peptides. They mostly permeate via tight junctions (paracellular pathway) in the intestine. This permeability mechanism restricts the magnitude of their oral absorption and bioavailability. We hypothesized that concealing the hydrophilic residues of the peptide using the lipophilic prodrug charge masking approach (LPCM) can improve the bioavailability of hydrophilic peptides. To test this hypothesis, a cyclic N-methylated hexapeptide containing Arg-Gly-Asp (RGD) and its prodrug derivatives, masking the Arg and Asp charged side chains, were synthesized. The library was evaluated for intestinal permeability in vitro using the Caco-2 model. Further investigation of metabolic stability ex vivo models in rat plasma, brush border membrane vesicles (BBMVs), and isolated CYP3A4 microsomes and pharmacokinetic studies was performed on a selected peptide and its prodrug (peptide 12). The parent drug analogues were found to have a low permeability rate in vitro, corresponding to atenolol, a marker for paracellular permeability. Moreover, palmitoyl carnitine increased the P

Phase II biotransformation reactions have been gaining more attention due to their acknowledged significance in drug bioavailability, drug development, and drug-drug interactions. However, the predominant role of phase I metabolism has always overshadowed phase II metabolism, resulting in insufficient data regarding its mechanisms. In this paper, we investigate the effect of an advanced lipid based formulation on the phase II metabolism process of glucuronidation, occuring in the enterocytes monolayer. The investigated formulation is a self-emulsifying drug delivery system, termed pro-nano lipospheres, which contains the natural absorption enhancer piperine. To evaluate the effect of this formulation on direct glucuronidation we chose the model molecule raloxifene. First, glucuronidation is the main clearance pathway of this compound without involvement of preceding mechanisms. Second, raloxifene's extensive glucuronidation site is primarily at the intestine. Raloxifene's oral bioavailability was determined in a series of pharmacokinetic experiments using the freely moving rat model. In order to test the effect of the formulation on the relevant UGT enzymes reported in the clinic, we used the in vitro method of UGT-Glo Assay. Coadministration of raloxifene and piperine pro-nano lipospheres to rats resulted in a 2-fold increase in the relative oral bioavailability of raloxifene. However, coadministration of raloxifene with blank pro-nano lipospheres had no effect on its oral bioavailability. In contrast to the difference found in vivo between the two vehicles, both formulations extended an inhibitory effect on UGT enzymes in vitro. Ultimately, these findings prove the ability of the formulation to diminish intestinal direct phase II metabolism which serves as an absorption obstacle for many of today's marketed drugs. Pro-nano lipospheres is a formulation that serves as a platform for the simultaneous delivery of the absorption enhancer and a required drug. The discrepancy found between the in vivo and in vitro models demonstrates that the in vitro method may not be sensitive enough to distinguish the difference between the formulations.

JS403 is a carbamoylphosphonate (CPO) molecule that showed anti-metastatic properties in mice. Since JS403 is intended to be a chronic prophylactic drug, the preferred route of administration should be oral. However, it exhibits poor oral bioavailability of less than 1%. The poor intestinal permeability and high solubility implies its classification as BCS class III drug. The aim of this study was to overcome the limited intestinal permeation of JS403 that is regarded as an unmet need in the pharmaceutical industry for this class of drugs. Therefore, the impact of acceptable absorption enhancers on the intestinal permeability of JS403 were examined using established experimental models. The absorption enhancers were: I) sodium caprate (C10), II) sodium deoxycholate (SDC) and III) mono-carboxymethylated chitosan (MCC). The effect of each enhancer was examined alone and also in combinations. In-vitro permeability through enterocytes monolayer was studied using the Caco-2 model, while the oral bioavailability was determined by using the freely moving rat model. The results of this investigation showed that while the use of a single absorption enhancer had no effect on JS403 permeability, the combination of C10 and sodium deoxycholate increased the permeability of JS403 by 10-fold in the in-vitro model. In addition, this blend showed a 2-fold elevation in JS403 oral bioavailability. Both in-vitro and in-vivo results highlight the synergistic potential of the combined enhancers C10 and sodium deoxycholate in enhancing oral bioavailability of BCS class III medications.

Thirty percent of top marketed drugs in the USA and 70% of all new drug candidates are lipophilic and exhibit poor water solubility. With such physicochemical properties, the oral bioavailability of these compounds lacks dose proportionality, is very limited and extremely erratic. Different lipid-based formulations have been explored in the past few decades to improve the oral delivery of such compounds. In recent years, the most popular approach is their incorporation into self-emulsifying drug delivery systems (SEDDS), with particular emphasis on self-nano-emulsifying drug delivery systems (SNEDDS).This review offers an updated overview of SNEDDS application from the biopharmaceutical point of view. The focus of this review deals with the potential of SNEDDS utilization to overcome absorption barriers following oral administration of lipophilic drugs. This includes a comprehensive description of the primary mechanisms by which lipids and lipophilic excipients, used to formulate SNEDDS, could affect drug absorption, bioavailability and disposition following oral administration.The utilization of SNEDDS to augment the oral bioavailability of poorly water-soluble drugs goes beyond improvement in drug's solubility, as was initially presumed. In fact, SNEDDS have a potential to increase oral bioavailability by multi-concerted mechanisms such as reduced intra-enterocyte metabolism by CYP P450 enzymes, reduced P-glycoprotein (P-gp) efflux activity and hepatic first-pass metabolism bypass via lymphatic absorption. This unique biopharmaceutical point of view, presented in this review, contributes to the understanding of proper drug candidate selection and of the approach in SNEDDS formulation design.

There is a growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metabolism. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex ® ). Fourteen healthy male volunteers received, on separate treatment days, either a single dose of PTL401 or an equivalent dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma C max than the equivalent dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of T max were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation.

Superior bioavailability of BCS Class 2 compounds incorporated into SNEDDS was previously reported. This study aims to elucidate the underlying mechanisms accountable for this phenomenon. SNEDDS of amiodarone (AM) and talinolol were developed. Pharmacokinetic parameters were assessed in vivo. Effect on intestinal permeability, P-gp efflux and toxicity was evaluated in vitro (Caco-2) and ex vivo (Ussing). Solubilization was assessed in vitro (Dynamic Lipolysis Model). Effect on intraenterocyte metabolism was evaluated using CYP3A4 microsomes. Oral administration of AM-SNEDDS and talinolol-SNEDDS resulted in higher and less variable AUC and Cmax. In vitro, higher talinolol-SNEDDS Papp indicated Pgp inhibition. Lipolysis of AM-SNEDDS resulted in higher AM concentration in the fraction available for absorption. Incubation of AM-SNEDDS with CYP3A4 indicated CYP inhibition. SNEDDS didn’t alter mannitol Papp and TEER. SNEDDS effect was transient. Multiple mechanisms are accountable for improved bioavailability and reduced variability of Class-2 compounds by SNEDDS: increased solubilization, reduced intraenterocyte metabolism and reduced P-gp efflux. SNEDDS effect is reversible and doesn’t cause intestinal tissue or cell damage. These comprehensive findings can be used for intelligent selection of drugs for which oral bioavailability will improve upon incorporation into SNEDDS, based on recognition of the drug’s absorption barriers and the ability of SNEDDS to overcome them.

During recent years there has been increasing interest in the Lycopodium alkaloid huperzine A as a potential therapeutic agent for neurodegenerative diseases. This study aimed to characterize huperzine A's permeability across the enterocyte barrier along the gastrointestinal tract with an emphasis on the effect of ionization on the drug absorption. Intestinal permeability of huperzine A was evaluated by in vitro Caco-2 and parallel artificial membrane permeation assay models and by the ex vivo Ussing chamber model. The permeability rate was strongly dependent on the degree of ionization and increased with elevation of the donor medium pH in all studied models. The transport of the unionized fraction was similar to the permeability of the markers for passive transcellular diffusion. Addition of the paracellular permeability modulator palmitoylcarnitine in the Caco-2 model led to significant enhancement in the permeability of the ionized huperzine A fraction. No evidence of active transport of huperzine A was detected in this study. The Ussing chamber model experiments showed similar drug permeability along the entire rat intestine. In conclusion, huperzine A permeates the intestinal border mainly by passive transcellular diffusion whereas some fraction, dependent on the degree of huperzine A ionization, is absorbed by the paracellular route. Huperzine A's permeability characteristics pave the way to the development of its oral extended release dosage form. The specific population of the potential users of huperzine A and the high potency of this molecule support the rationale for such a delivery.

Background Amphotericin-B (AMB) is associated with toxicity such as renal impairment, hypokalemia and infusion-related events (IRE). With the advent of AMB lipid formulations and newer antifungal drugs, presenting improved safety profiles, it was suggested that using the conventional deoxycholate (AMB-D) formulation should no longer be regarded acceptable. Objectives Evaluation of real-life incidence of AMB-D-related adverse-drug effects (ADE) and associated costs. Setting Hadassah Hebrew University Medical Center, Jerusalem, Israel, a tertiary 1,100-bed teaching hospital. Methods A 1-year single-center prospective observational study following all patients administered AMB-D. Various parameters related to AMB-D administration were recorded. Main outcome measures Subsequent ADE-related events, discontinuations, switch to alternative antifungals and related resource-utilization were monitored. Results Among 119 patients (60 children, 59 adults) receiving AMB-D, serum creatinine doubling from baseline, hypokalemia and IRE occurred in 14.3 % (15 % in children, 13.6 % in adults), 16.8 % (16.6 % in children, 16.9 % in adults) and 10.9 % (10 % in children, 11.8 % in adults), respectively. AMB-D was discontinued due to an ADE in 12.6 % of patients (6.7 % in children, 18.6 % in adults). The total annual cost associated with AMB-D use was €58,600. Conclusion The clinical as well as economic burden of AMB-D associated ADE, as observed in real-life settings, appears to be manageable. Considering the significant cost implications associated, as suggested by simulated evaluation of an overall theoretic replacement of AMB-D by an equivalent volume of alternative antifungals, total abandonment of AMB-D appears unjustified.

Objective Preparation and characterization of an oral pro-dispersion liposphere formulation for cyclosporin, a water insoluble drug with limited bioavailability. Methods Pro-dispersion formulation consisted of a solid fat, dispersing agents and amphiphilic solvents as the major components besides cyclosporin A (CsA) were prepared in the present work. For preparation of this formulation, phospholipid was dissolved in pharmaceutically acceptable water soluble organic solvent, thereafter CsA along with other components was added and formulation optimization was carried out. After formulation preparation, particle size determination and in vitro release study was carried out. Additionally, ultracentrifugation, TEM, Cryo-TEM and DSC techniques were used for in vitro characterization of formulation. The prepared system was also compared with marketed Neoral® microemulsion formulation. Results Liposphere formulations were prepared and optimized as according to procedure. Though, determination of in vitro characteristics of such formulations is complex and difficult, yet selected and performed tests confirmed formation and existence of solid liposphere particles upon dispersion of formulation in water. It was also observed that particle size is influenced by the type of solid fat used and amphiphilic solvent present in the formulation. Prepared pro-dispersion was found to be stable for 2 years under normal storage conditions. Conclusion Prepared pro-dispersion liposphere formulation is a homogeneous solution of a lipophilic drug such as cyclosporin in a mixture of surfactants, lipids and ethyl lactate proved to spontaneously form dispersion when added to aqueous media. This formulation concept has a potential clinical use for improved bioavailability of water insoluble drugs.

Rheumatoid arthritis (RA) is a common human leukocyte antigen-associated disease. Most RA patients have a five-residue sequence motif called the shared epitope (SE) in the DRβ-chain of the HLA-DRB1 protein. The SE was found to activate nitric oxide (NO) production, suggesting a possible mechanism for RA development. The native conformation of the SE is presumed to be an α-helix, thus using cyclic peptides to stabilize this conformation may produce a potent SE mimetic which will have drug- like properties. We present the development of a backbone cyclic SE mimetic that activates NO production in the low nM range. Circular dichroism analysis revealed a conformational change from unstructured for the parent linear peptides to β– turn in the cyclic analogs. The most active cyclic analog is completely stable towards trypsin/chymotrypsin degradation while the linear 15-mer analogs completely degraded within 30 minutes. The outcome of this study is a potent cyclic peptide with drug-like properties that can be used as a template for drug development.

Recent progress in peptide synthesis simplified the synthesis of multiple N-methylation of peptides. To evaluate how multiple N-methylation affects the bioavailability of peptides, a poly alanine cyclic hexapeptide library (n = 54), varying in the number of N-methyl (N-Me) groups (1-5 groups) and their position, was synthesized. The peptides were evaluated for their intestinal permeability in vitro using the Caco-2 model. Further evaluation of the transport route of chosen analogues was performed using rat excised viable intestinal tissue, a novel colorimetric liposomal model and the parallel artificial membrane permeability assay (PAMPA). While most members were found to have poor permeability (permeability coefficient, P(app)1 x 10⁻⁶ cm/s, lower than mannitol, the marker for paracellular permeability), 10 analogues were found to have high Caco-2 permeability, (P(app)1 x 10⁻⁵ cm/s, similar to testosterone, a marker of transcellular permeability). No correlation was found between the number of N-methylated groups and the enhanced permeability. However, 9/10 permeable peptides in the Caco-2 model included an N-Me placed adjacently to the D-Ala position. While the exact transport route was not fully characterized, the data suggests a facilitated diffusion. It can be concluded that multiple N-methylation of peptides may improve intestinal permeability, and therefore can be utilized in the design of orally available peptide-based therapeutics.

A quasi-equilibrium mass transport analysis has been developed to quantitatively explain the solubility-permeability interplay that exists when using cyclodextrins as pharmaceutical solubilizers. The model considers the effects of cyclodextrins on the membrane permeability (P(m)) as well as the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on cyclodextrin concentration (C(CD)). The analysis reveals that: (1) UWL permeability markedly increases with increasing C(CD) since the effective UWL thickness quickly decreases with increasing C(CD); (2) membrane permeability decreases with increasing C(CD), as a result of the decrease in the free fraction of drug; and (3) since P(aq) increases and P(m) decreases with increasing C(CD), the UWL is effectively eliminated and the overall P(eff) tends toward membrane control, that is, P(eff) approximately P(m) above a critical C(CD). Application of this transport model enabled excellent quantitative prediction of progesterone P(eff) as a function of HP beta CD concentrations in PAMPA assay, Caco-2 transepithelial studies, and in situ rat jejunal-perfusion model. This work demonstrates that when using cyclodextrins as pharmaceutical solubilizers, a trade-off exists between solubility increase and permeability decrease that must not be overlooked; the transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.

A peptide–peptoid hybrid (peptomer) library was designed and synthesized, based on the sequence Phe- d -Phe-Arg-Trp-Gly. This sequence was previously found to specifically activate the melanocortin-4-receptor (MC4R) which participates in regulation of energy homeostasis and appetite. The library of peptomers included a peptoid bond in the Phe and/or d -Phe position and consisted of linear and backbone cyclic analogs, differed in their ring size. While the linear peptides rapidly degraded in serum and in brush border membrane vesicles (BBMV’s), the linear peptomers were more stable. Backbone cyclic peptomers were also stable under the same conditions. Backbone cyclization significantly increased the intestinal permeability of two peptomers compared to their linear counterparts, in the Caco-2 model. Pharmacological evaluation revealed that two linear and one backbone cyclic peptomer, were found active towards MC4R at the nanomolar range. Thus, the conformational constrains imposed by these local and global modifications affect both the pharmacokinetic and pharmacodynamic properties of the parent peptide. This study demonstrates the potential of imposing backbone cyclization on bioactive peptomers as a promising approach in developing an orally available peptidomimetic drug leads.

Tetraphenylphosphonium (TPP), a phosphonium cation, is a promising means for tumor imaging. A major contributor to the pharmacokinetics of phosphonium cations is the efflux transporter P-glycoprotein (P-gp). For this application it is important to ascertain the influence of the multidrug resistance system on TPP. Therefore, our aim was to characterize the interaction of TPP with P-gp, in vitro and in in vivo models. P-gp-mediated transport of [3H]-TPP was assessed in Caco-2 cells and ex vivo in rat intestinal wall by the use of a diffusion cell system. The distribution of [3H]-TPP across the blood-brain barrier (BBB) was studied in rats and mice treated with P-gp modulators and in Mdr-1a/b((-/-)) knockout mice. The in vitro permeability coefficient of basolateral-to-apical transfer (PappB-A) of [3H]-TPP was 8-fold greater than apical-to-basolateral (PappA-B) coefficient, indicative of net mucosal secretion. A concentration dependent decrease of this secretion was obtained by the P-gp substrate verapamil, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC. [3H]-TPP transfer across rat jejunum wall was directional and concentration-dependent. 2,4-Dinitrophenol, cyclosporin A (CsA), verapamil and PSC-833 enhanced A-B transport of TPP 3.6-fold, 4-fold, 4.6-fold and 5.3-fold respectively. Likewise, PappA-B of [3H]-TPP was 5-fold greater in P-gp knockout mice than in controls. In vivo, PSC-833, P-gp inhibitor, significantly increased the uptake of [3H]-TPP in the liver, heart, small intestine and the lungs but not the brain. Similar results were obtained in P-gp knockout mice. Our study demonstrates that P-gp mediates TPP efflux in vitro and in vivo; however, the consistently poor BBB permeation of TPP in all in vivo studies including P-gp knockout animals indicates that it is most likely mediated by other mechanisms. These findings are important for optimized clinical application of TPP as an imaging agent in cancer.

Gastro-retentive dosage form (GRDF) is a controlled-release modality of drug delivery technology that allows continuous administration to the upper part of the gastrointestinal tract. The manuscript summarizes various aspects that should be considered for the successful implementation of these region-specific delivery systems, including underlying physiological principles, technologies, and performance assessment approaches. In particular it focuses on characterization of potential drug candidates for GRDF and the anticipated pharmacokinetic and pharmacodynamic advantages associated with GRDF administration. These considerations are demonstrated using gabapentin as a representative narrow absorption window drug. The pharmacokinetic model that was developed for description of oral absorption of gabapentin in humans included variable intragastric input functions, saturable absorption kinetics and limited absorption window in the proximal gut. The pharmacokinetic profiles obtained via simulation demonstrated the potential benefits that can be accomplished by GRDF for gabapentin, including dose-proportional absorption, extended duration of absorption and thereby reduced dosing frequency and lowered total daily dose. Such pharmacokinetic modeling and simulation are shown to be an important and useful tool that can be used to optimize the selection of the mode of oral drug administration, including GRDF approach.

The purpose of this study was to evaluate the impact of general anesthesia on the lymphatic transport of orally administered drugs. Vitamin D 3 (0.5 mg/kg), a model lipophilic molecule with significant lymphatic transport, was administered to anesthetized rats in close proximity to the lymphatic cannulation procedure. The lymphatic and non-lymphatic absorption of the vitamin in this experimental model was compared to lymph-duct cannulated freely moving conscious rats. The amounts of vitamin D 3 transported via the lymph in the anesthetized animals throughout the time frame of this experimental model (8 h) were 25% lower as compared to the conscious animals, but showed similar absorption kinetics. However, the duration of the anesthesia is limited and thus failed to produce the complete picture of the absorption process. The cumulative percent of the vitamin dose that was recovered in the lymph as well as the vitamin plasma AUC values were both 25% lower in the anesthetized animals as compared to the conscious animals. Hence, the anesthesia did not influence the proportion of the vitamin fraction absorbed via the different pathways. The lymph flow rate was significantly decreased by the anesthesia (threefold), however, higher lymph vitamin concentrations in these animals led to lower differences in the vitamin lymphatic transport (25%) between the models. In conclusion, the anesthetized rat model is suitable for approximating the lymphatic transport. However, the conscious rat model is still required in order to have a more precise and complete measurement of lymphatic transport.

To assess the effects of the unabsorbed fraction of an orally administered antimicrobial drug which enters the colon on the emergence of resistance among the natural microflora, a phenomenon largely overlooked so far despite its clinical importance, especially when sustained release formulations are used.Effects of an orally administered model beta-lactam antibiotic (amoxicillin) on emergence of resistant bacteria were assessed using a microbiological assay for qualitative and quantitative determination of resistant bacteria in fecal samples of rats following gastric administration of the drug to rats for 4 consecutive days. Time- and site-controlled administration of a beta-lactamase to the rat colon was assessed as a potential strategy for prevention the emergence of resistant bacteria following oral administration of incompletely absorbed antimicrobials.Emergence of resistant bacteria was demonstrated following oral administration of amoxicillin to rats, whereas de-activation of the beta-lactam prior to entering the colon, by infusion of a beta-lactamase into the lower ileum, was shown to prevent the emergence of resistant colonic bacteria.This study illustrates the need to consider the emergence of antimicrobial resistance as a goal equally important to microbiological and clinical cure, when designing oral sustained-release delivery systems of antimicrobial drugs.

Following a high-fat meal, triglyceride-rich lipoproteins (TRL) are assembled in the gut and absorbed via the lymph into the blood circulation, producing a temporal hyperlipidemia. The purpose of this study is to verify the hypothesis that this transient acute postprandial hyperlipidemia affects the pharmacokinetics of lipophilic drugs on both absorption and disposition levels by the same underlying mechanism, namely the association of active lipophilic compounds with TRL in the plasma (disposition) or within the enterocyte (lymphatic transport). This concept was assessed in rats using two model compounds, DDT with high affinity to chylomicrons and diazepam which does not bind to chylomicrons. Oral administration of peanut oil significantly increased the AUC of plasma DDT concentrations following its IV bolus administration in comparison to a water treated group. On the other hand, the AUC of diazepam following IV bolus administration was the same in oil and water treated rats. While DDT is known to have significant lymphatic bioavailability, diazepam has negligible intestinal lymphatic transport (0.014+/-0.004% of a given dose). In conclusion, lipophilic molecules that bind extensively to TRL will be prone to both intestinal lymphatic transport and to post-absorptive changes in disposition (decrease in clearance and volume of distribution) following a high-fat meal.

The aim of this article was to investigate the role of intestinal lymphatic transport in the oral bioavailability of two structurally similar synthetic lipophilic cannabinoids: dexanabinol and PRS-211,220. For this purpose, the long chain triglyceride (LCT) solubility and affinity to chylomicrons ex vivo of both cannabinoids were evaluated. Their oral bioavailability was assessed in rats following administration in a lipid-free and a LCT-based formulation. The intestinal lymphatic transport of these two molecules was also directly measured in a freely moving rat model. LCT solubility of dexanabinol and PRS-211,220 was 7.9 ± 0.2 and 95.8 ± 5.3 mg/g, respectively. The uptake by chylomicrons was moderate (31.6 ± 5.2%) and high (66.1 ± 2.4%), respectively. The bioavailability of dexanabinol (37%) was not affected by LCT solution, whereas administration of PRS-211,220 in LCT improved the absolute oral bioavailability three-fold (from 13 to 35%) in comparison to the lipid-free formulation. The intestinal lymphatic transport of dexanabinol and PRS-211,220 was 7.5 ± 0.8 and 60.7 ± 6.8% of the absorbed dose, respectively. In conclusion, despite structural similarity and similar lipophilicity, dexanabinol and PRS-211,220 exhibited a very diverse pattern of oral absorption, and the lymphatic system played quite a different role in the oral bioavailability of these molecules. The low lymphatic transport of dexanabinol is likely driven by relatively lower affinity to chylomicrons and lower LCT solubility.

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.

Nonsteroidal anti-inflammatory drugs, including indomethacin, have been found in both epidemiological and clinical studies to reduce the prevalence and severity of Alzheimer's disease. However, long-term use of indomethacin is limited by significant gastrointestinal and renal toxicities. An indomethacin prodrug that delivers low and continuous blood levels of the drug showed a superior safety profile and similar efficacy in comparison to an equivalent dose of free indomethacin because of limited systemic exposure and preferred brain uptake. The purpose of the present investigation was to evaluate whether sustained systemic input causes an increased brain influx in comparison to rapid input of the drug. Oral indomethacin, indomethacin prodrug, or intravenous indomethacin infusion was administered to rats. The infusion was designed to mimic the plasma indomethacin levels resulting from the prodrug. The resultant blood levels and brain indomethacin uptake were evaluated. The brain indomethacin concentrations 8 h following indomethacin administration were 0.45, 0.3, and 0.31 microg/g after the oral indomethacin, oral prodrug, and intravenous infusion, respectively. The corresponding plasma concentrations were 14.1, 4.1, and 4 microg/ml. Therefore, brain versus plasma indomethacin level ratios were 2.5-fold higher after slow systemic input of indomethacin in comparison to rapid drug input. In conclusion, indomethacin brain uptake was found to be mode of administration-dependent, and a sustained input function increases the drug brain uptake. Thus, these unique results indicate that an appropriate indomethacin controlled release delivery system may induce the desirable brain-related pharmacodynamic effects, while avoiding the concentration-dependent adverse effects. These findings may contribute to improved therapy in Alzheimer's disease.

To examine the correlation between the in vitro solubilization process of lipophilic compounds from different lipid solutions and the corresponding in vivo oral bioavailability data. In particular, to assess the influence of intra-enterocyte processes (metabolism and lymphatic absorption) on this correlation. The dissolution of progesterone and vitamin D3 in long (LCT), medium (MCT) and short (SCT) chain triglyceride solutions were tested in a dynamic in vitro lipolysis model. The absolute oral bioavailability of the drugs from the tested formulations was investigated in rats. Vitamin D3 bioavailability was also examined following lymphatic transport blockage induced by cycloheximide (3 mg/kg). The dynamic in vitro lipolysis experiments indicated a rank order of MCT > LCT > SCT for both progesterone and vitamin D3. The bioavailability of progesterone correlated with the in vitro data, despite its significant pre-systemic metabolism. For vitamin D3, an in vivo performance rank order of LCT > MCT > SCT was obtained. However, when the lymphatic transport was blocked the bioavailability of vitamin D3 correlated with in vitro data. The in vitro lipolysis model is useful for optimization of oral lipid formulations even in the case of pre-systemic metabolism in the gut. However, when lymphatic transport is a significant route of absorption, the in vitro lipolysis data may not be predictive for actual in vivo absorption.

The purpose of this study was to evaluate the ability of the Accordion Pill (AP), a novel controlled release gastroretentive unfolding dosage form (DF), to increase the bioavailability of riboflavin (RF) in humans. Three formulations containing 75 mg of RF and differing in release rate (immediate release (IR) capsule, AP#1, and AP#2) were administered with a low-calorie meal. Gastric residence time (GRT) of the AP was assessed by magnetic resonance imaging. Serial blood and urine samples were taken and assayed for RF. The AP demonstrated prolonged (up to 10.5 h) GRT in humans. Significant elevation in RF bioavailability (209+/-37%, mean+/-S.E.) was achieved by the AP#1 in comparison to the IR capsule. A correlation was established between the in-vitro release rates from DF and bioavailability of RF in humans, and it was modeled taking into account the saturable nature of RF absorption transport and its narrow absorption window (NAW) in the upper gastro-intestinal tract. It is anticipated that the AP will provide a valuable pharmaceutical solution to enhance therapy with NAW drugs.

Oral administration of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) has been reported to increase the bioavailability of various macromolecules. The present study was aimed to study the effect of SNAC on the intestinal tissue permeability of polar charged molecules, using 6-carboxy-fluorescein (6-CF) as a model. The effects of SNAC on rat intestinal permeability was investigated ex vivo by utilizing voltage clamp experiments in a side-by-side diffusion chamber model in comparison with the effect of EDTA (10mM). The intestinal permeability of 6-CF was increased two-fold in the presence of 33-66 mM SNAC, and by 6.5-fold in the presence of 10mM EDTA. The voltage clamp experiments show that the effect of SNAC was particularly on the transcellular 7-folds increase (that was five times larger than the paracellular transport of the model agent). While EDTA affected predominantly paracellular pathway transport, SNAC 33-66 mM had no effect on [(3)H]-mannitol transport or any toxic effect on tissue integrity measured by TEER values. In conclusion, this study demonstrates that SNAC can facilitate passive transport of polar charged molecules through the membrane of epithelial enterocytes. This is noteworthy in view of the very low tendency of a charged molecule to permeate across the lipophilic inter-phase of the enterocytes membrane.

The purpose of this study was to examine the feasibility of investigating the lymphatic transport of drugs in vivo utilizing known chylomicron flow blocking substances. Vitamin D(3) (0.5 mg/kg), a model lipophilic molecule, was administered to rats with blocked chylomicron flow, induced by either cycloheximide injection (3 mg/kg), colchicine injection (5 mg/kg) or intraduodenal infusion of pluronic L-81 (1 mg/h). The effect of these experimental models on the absorption of Vitamin D(3) was compared to the outcomes of the mesenteric lymph duct cannulated rat model. The oral d-xylose loading test was used to verify that other intestinal absorptive functions were not affected. Colchicine treatment induced severe adverse effects whereas pluronic L-81 and the cycloheximide models did not affect other absorption pathways and did not cause apparent adverse effects. Vitamin D(3) absorption in these two models was in good correlation to the mesenteric lymph duct cannulation model (25% non-lymphatic relative bioavailability) indicating that the incorporation of the lipophilic molecule into the chylomicron is an essential step in the cascade of lymphatic absorption. Moreover, the data suggest that the drug association with the chylomicron occurs at an early stage of its assembly process. The results also specify that lymphatic absorption and portal blood absorption are separate pathways that are not affected by each other. In conclusion, the chemical blockage of chylomicron flow provides a potential approach for lymphatic transport investigation, and may elucidate processes involving in the absorption of lipophilic compounds.

Expandable gastroretentive dosage forms (GRDFs) have been designed for the past 3 decades. They were originally created for possible veterinary use, but later the design was modified for enhanced drug therapy in humans. These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention time (GRT). After drug release, their dimensions are minimized with subsequent evacuation from the stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. Positive results were obtained in preclinical and clinical studies evaluating GRT of expandable GRDFs. Narrow absorption window drugs compounded in such systems have improved in vivo absorption properties. These findings are an important step towards the implementation of expandable GRDFs in the clinical setting. The current review deals with expandable GRDFs reported in articles and patents, and describes the physiological basis of their design. Using the dog as a preclinical screening model prior to human studies, relevant imaging techniques and pharmacokinetic-pharmacodynamic aspects of such delivery systems are also discussed.

Purpose. To design novel expandable gastroretentive dosage forms (GRDFs) and evaluate their gastroretentive properties. Then, to assess the pharmacokinetics of levodopa compounded in such a GRDF in healthy volunteers. Methods. Thin (

Metformin, a commonly used antidiabetic drug, exerts its glucose-lowering effect due to metabolic activities at several sites of action (biophases), including liver, intestine, muscle cells, and adipocytes. The relative contribution of the individual biophases to the overall glucose-lowering effect is not known. Thus, the aims of this investigation were to study the influence of mode of drug administration on the kinetics of glucose-lowering action of metformin in diabetic rats and identify the contribution of different sites of action to the overall response. Streptozotocin diabetic rats received metformin in crossover fashion via intraduodenal, intravenous, and intraportal routes as bolus dose or infusion regimens designed to yield similar pharmacokinetic profiles. Metformin plasma concentrations and blood glucose levels were measured following each mode of administration. Despite the similarity in the concentration-time profiles obtained for different routes of metformin administration, intraduodenal administration produced larger response than intraportal metformin infusion, and lowest response was observed following intravenous administration. This finding indicates that a significant "first-pass" pharmacodynamic effect, which occurs in the presystemic sites of action (liver and the gastrointestinal wall), contributes to the overall glucose-lowering response of metformin. We applied a combined pharmacokinetic-pharmacodynamic modeling approach to study the nature of the first-pass pharmacodynamic effect. The observed data were successfully described by a novel integrated indirect response pharmacokinetic-pharmacodynamic model that revealed a correlation between the temporal metformin concentrations that transit the portal vein and through the gut wall rather than with drug concentrations that accumulated in the liver and the intestinal wall.

Objective To determine what triggers the use of digoxin therapeutic drug monitoring (TDM) that adheres to established indications and the change in digoxin dosage after the result of monitoring is obtained. Methods This prospective study included 86 patients admitted to 6 medicine wards and 2 intensive cardiac care unit wards in a tertiary-care center. Data on patients' demographics, drug therapy, serum chemistry values, indications for digoxin therapy, indications for ordering the drug assay, timing of the blood sample relative to administration of the last dose, and physicians' decisions after attaining serum digoxin concentrations were collected. Results Eighty-six digoxin assays were evaluated. Indications for the use of a digoxin assay were mostly routine without a clear indication (66%); in only 22% of the assays were orders considered clinically justified. Eleven patients had concentrations >2 ng/mL, but only 8 patients had digoxin intoxication. In only 31% of patients did the medical staff respond to the results. In only 21% of patients with subtherapeutic drug concentrations was there a change in digoxin dose. Conclusions Although there are clear indications for the use of digoxin TDM, physicians seem to routinely order these blood tests. The clinicians did not adequately use the digoxin concentration data to optimize therapy. The assistance of a clinical pharmacist or pharmacologist is warranted for use of the assays, to optimize digoxin therapy.

We studied the differences in pharmacokinetics and pharmacodynamics of the same dose of alendronate administered subcutaneously as intermittent bolus injection or continuous infusion in rats. Two rat models of bone disease were applied. Bone cancer was produced by intratibial inoculation of Walker carcinosarcoma cells, and a model of augmented bone resorption was produced by vitamin D(3) treatment of rats that had undergone thyroidparathyroidectomy. Higher amounts of alendronate were found in bones and in internal organs after bolus drug administration as compared with continuous infusion. Drug effects on plasma calcium levels and on urine calcium excretion were similar in both modes of alendronate administration. Results of the study indicate that the pharmacokinetics (disposition) of alendronate is administration-dependent. The total amount found in bone does not directly represent the amount of alendronate that is pharmacologically active at the site of action in the bone and that affects bone remodeling. The findings suggest that there is no pharmacodynamic advantage for continuous infusion of alendronate. It is concluded that the preferred mode of administration should be selected according to secondary clinical criteria (like incidence of adverse effects and convenience of administration).

Purpose. The purpose of this study was to design novel gastroretentive dosage forms (GRDFs) based on unfolding multilayer polymeric films, to investigate the mechanism of their gastroretentivity in dogs, and to assess the effect of compounding a narrow absorption window drug in a GRDF on the drug's absorption properties.

We examined the pharmacokinetic (PK) and pharmacodynamic (PD) rationales to develop controlled release (CR) formulations of metformin. Unrestrained diabetic rats received the drug as intravenous bolus (i.v.), oral solution (p.o.), intra-duodenal bolus, 4-h infusion, or intra-colonic bolus. In addition, we developed two CR-gastroretentive dosage forms (CR-GRDF) that released the drug over 3 or 6 h (in vitro), and retained in the rats’ stomach for 8–10 h. Metformin exhibited flip-flop PK. The colonic absorption was low but sustained and was associated with highly variable glucose-lowering effects, thus providing a PK rationale to develop CR-GRDF. In addition, the glucose-lowering effect was greater following p.o. vs. i.v. administration, despite equivalent AUC, indicating a first pass PD effect, thus, adding a PD rationale to develop metformin CR-GRDF. When administered to the diabetic rats, CR-GRDFs produced bioavailability and extent of glucose-lowering effects that were similar to those of the duodenal infusion and p.o. metformin administration. These findings are attributed to the adsorption of metformin to the intestine that yields slow and prolonged absorption even following p.o. administration of drug solution. The data indicates that unless the CR formulation could significantly extend the absorption period, it is not likely to improve glucose-lowering efficacy.

Purpose. To utilize power spectral analysis (PSA) of heart rate variability (HRV) as a pharmacodynamic (PD) measure of atropine parasympathetic effect, and to model the kinetics of action.

The goal of this investigation was to optimize antilipid therapy by utilizing the combined activity of two lipid-lowering agents, niacin and bezafibrate, and improve their efficacy by targeting them to their presumed presystemic site(s) of action. Thus, continuous duodenal (IGI) administration of the drug combination should augment their efficacy in comparison with intermittent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on on acute hyperlipidemia induced by triton injection. Continuous IGI administration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg/kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced significantly greater lowering of total cholesterol and triglycerides and elevation of high-density lipoprotein (HDL) cholesterol in comparison with intermittent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafibrate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix tablet of the drug combination resulted in a similar magnitude of effect as the IGI administration, the present study provides a pharmacodynamic rationale for the use of a slow-release low-dose niacin-bezafibrate combination.

Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug.

Purpose. To validate our hypothesis that a bisphosphonate (BP) having a nitrogen-containing heterocyclic ring on the side chain, and with no hydroxyl on the geminal carbon would possess increased activity, and better oral bioavailability due to enhanced solubility of its calcium complexes/salts and weaker Ca chelating properties.

The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia—Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg−1). Continuous administration of niacin into the duodenum at 1.66 mg h−1 (total dose 40 mg kg−1 day−1) for up to 7 days (Model A) or at 2.22 mg h−1 over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15–25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg−1) has a greater lipid-lowering effect than a higher dose (200 mg kg−1) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.

High molecular weight drugs in general, and peptides/proteins in particular, are usually delivered by parenteral routes because they are poorly absorbed or degraded in the gastrointestinal tract. Long-term, repeated injections are often required because of the drug's short half-life, and the chronic nature of many diseases. To optimize therapy, it is essential to search for a non-parenteral route of drug administration. We describe here the absorption and the systemic biological effect of model drugs, after instillation into the uterus of the rat. In addition, we describe here results of calcitonin and insulin absorption from controlled-release devices inserted in the rat uterus. The amount and duration of the hypoglycemic and the hypocalcemic effects induced by intrauterine delivery of insulin and calcitonin, respectively, were equivalent to those obtained after subcutaneous injections. The therapy of a number of clinically important diseases could benefit from this discovery.

Fine, homogeneous, positively-charged emulsions with a mean droplet size of 138 ± 71 nm and a zeta potential value of 41.06 mV were prepared using a combination of emulsifiers comprising phospholipids, poloxamer 188, and stearylamine. The pH of these emulsions decreased with time. However, the extent of decrease was dependent on the storage temperature. The mean droplet size of the emulsions that had been prepared with 1% poloxamer began to increase slightly after six months’ storage, particularly when stored at 23 and 37°C. However, emulsions prepared with 2% poloxamer remained stable for at least 10 months at 4°C, suggesting that the poloxamer 188 concentration is critical for prolonged emulsion stability. The results of the ocular tolerance study in rabbit eye indicate that hourly administration of a positively-charged emulsion vehicle was well tolerated without any toxic or inflammatory response to the ocular surface during the five days of the study. Scanning electron microscopy revealed a normal corneal surface, which was not different from that of the animals treated with physiological saline. No marked acute toxicity was observed when 0.6 mL of positively-charged emulsion was injected intravenously to BALB/c mice. Furthermore, no difference was noted between this group of animals and the group injected with the marketed Intralipid emulsion. These results were further confirmed in a rat study where there were no deaths following intravenous injection of 3.3 mL per rat of the positively-charged emulsion or Intralipid. Neither emulsion elicited any hepatotoxic or nephrotoxic effects. The overall results suggest that the novel positively-charged emulsion is suitable for parenteral use, and for ocular application.

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.