Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms.

Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the "magic bullets" concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know-how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products.

Towards Effective Antiviral Oral Therapy: Development of a Novel Self-Double Emulsifying Drug Delivery System for Improved Zanamivir Intestinal Permeability.

Self-double emulsifying drug delivery systems have the potential to enhance the intestinal permeability of drugs classified under the Biopharmaceutics Classification System (BCS) class III. One such example is the antiviral agent zanamivir, exhibiting suboptimal oral absorption (with a bioavailability range of 1-5%). To address this challenge, we have developed an innovative oral formulation for zanamivir: a self-double nanoemulsifying Winsor delivery system (SDNE-WDS) consisting of the microemulsion, which subsequently yields final double nanoemulsion (W1/O/W2) upon interaction with water. Two distinct formulations were prepared: SDNE-WDS1, classified as a W/O microemulsion, and SDNE-WDS2, discovered to be a bicontinuous microemulsion. The inner microemulsions displayed a consistent radius of gyration, with an average size of 35.1 ± 2.1 nm. Following self-emulsification, the resultant zanamivir-loaded nanoemulsion droplets for zSDNE-WDS1 and zSDNE-WDS2 measured 542.1 ± 36.1 and 174.4 ± 3.4 nm, respectively. Both types of emulsions demonstrated the ability to enhance the transport of zanamivir across a parallel artificial membrane. Additionally, in situ rat intestinal perfusion studies involving drug-loaded SDNE-WDSs revealed a significantly increased permeability of zanamivir through the small intestinal wall. Notably, both SDNE-WDS formulations exhibited effective permeability (Peff) values that were 3.5-5.5-fold higher than those of the low/high permeability boundary marker metoprolol. This research emphasizes the success of SDNE-WDSs in overcoming intestinal permeability barriers and enabling the effective oral administration of zanamivir. These findings hold promise for advancing the development of efficacious oral administration of BCS class III drugs.

Enabling oral delivery of antiviral drugs: Double emulsion carriers to improve the intestinal absorption of zanamivir.

Antiviral drugs play a major role in the control of seasonal influenza epidemics and may provide prophylactic and therapeutic benefits during an eventual pandemic. Among the neuraminidase inhibitors, zanamivir has been shown to be a potent inhibitor of influenza viruses, and similarly against emerging resistant strains. Despite its high antiviral efficiency, zanamivir suffers from poor intestinal permeability, therefore administered via inhalation. Enabling oral delivery of zanamivir will augment the available antiviral tools in clinical practice, increase patient compliance and ultimately improve public health. Encapsulation of hydrophilic drugs within double emulsions (DEs), is an efficacious approach to enhance the oral bioavailability of BCS Class III drugs, such as zanamivir. The objective of this research was to increase the intestinal absorption of zanamivir by means of compatible DEs. Two different types of stable DEs were prepared comprising different internal aqueous phases (W1). These micro-sized DEs showed high encapsulation efficacy (96.6-98.9 %) and markedlyretardedtherelease rateof the antiviral drug. Both types of the zanamivir loaded DEs (zDEs) significantly increased the transport ability of zanamivir across a parallel artificial membrane. Furthermore, in-situ perfusion of zDEs revealed outstanding permeability of zanamivir across the intestinal wall of rats. The zDEs containing carbomer gel (rather than carboxymethyl cellulose) as W1 obtained superior in-vivo effective permeability (Peff); yet, both zDEs exhibited higher Peff values (2-6-fold) than the low/high permeability marker (metoprolol). In conclusion, the DEs delivery system allowed overcoming the intestinal permeability barriers, towards successful oral administration of zanamivir.

The role of various transporters in the placental uptake of ofloxacin in an in vitro model of human villous trophoblasts.

INTRODUCTION: Six years after the US Food and Drug Administration approval of the broad-spectrum antibiotic ofloxacin (OFLX), the chiral switching of this racemic mixture resulted in a drug composed of the L-optical isomer levofloxacin (LVFX). Since both fluoroquinolones (FQs) were introduced to the pharmaceutical market, they have been widely prescribed by physicians, with careful administration during pregnancy and breastfeeding. Therefore, the role of the influx and efflux placental transporters in the concentrations of these drugs that permeate through human placental barrier model was investigated in this study. METHODS: The contribution of major carriers on the transplacental flux of OFLX and LVFX uptake into choriocarcinoma BeWo cells was evaluated in the presence vs absence of well-known inhibitors. RESULTS: Our results reveal that neither the influx transporters such as organic cation transporters, organic anion transporters, and monocarboxylate transporters nor the efflux transporters such as P-glycoprotein or breast cancer resistance protein significantly affected the transport of OFLX. In contrast, multiple transporters revealed pronounced involvement in the transfer of the levorotatory enantiomer in and out of the in vitro placental barrier. These data suggest a non-carrier-mediated mechanism of transport of the racemic mixture, while LVFX is subjected to major influx and efflux passage through the placental brush border membranes. CONCLUSION: This study provides underlying insights to elucidate the governing factors that influence the flux of these FQs through organ barriers, in view of the controversial safety profile of these drugs in pregnant population.

Dermal absorption behavior of fluorescent molecules in nanoparticles on human and porcine skin models.

The percutaneous passage of poorly skin absorbed molecules can be improved using nanocarriers, particularly biodegradable polymeric nanospheres (NSs) or nanocapsules (NCs). However, penetration of the encapsulated molecules may be affected by other factors than the nanocarrier properties. To gain insight information on the skin absorption of two fluorescent cargos, DiIC18(5) and coumarin-6 were incorporated in NSs or NCs and topically applied on various human and porcine skin samples. 3D imaging techniques suggest that NSs and NCs enhanced deep dermal penetration of both probes similarly, when applied on excised human skin irrespective of the nature of the cargo. However, when ex vivo pig skin was utilized, the cutaneous absorption of DiIC18(5) was more pronounced by means of PLGA NCs than NSs. In contrast, PLGA NSs noticeably improved the porcine skin penetration of coumarin-6, as compared to the NCs. Furthermore, the porcine skin results were reproducible when triplicated whereas from various human skin samples, as expected, the results were not sufficiently reproducible and large deviations were observed. The overall findings from this comprehensive comparison emphasize the potential of PLGA NCs or NSs to promote cutaneous bioavailability of encapsulated drugs, exhibiting different physicochemical properties but depending on the nature of the skin.

A mechanistic approach to understanding oral drug absorption in pediatrics: an overview of fundamentals.

The common phrase 'children are not little adults' is very true also in the field of oral drug administration and absorption. However, in practice, due to the little available data and lack of in-depth understanding, physicians may treat kids as if they were 'little adults', even without being aware of the potential differences and risks. With respect to drug discovery, research and development, an in-depth understanding of the various factors governing age-dependent absorption is crucial when trying to develop a pediatric-tailored oral drug product. In this paper we clarify the various mechanisms that may lead to age-dependent oral drug absorption, we provide an overview of the currently available data, and draw conclusions to the coming years.

Enhanced cutaneous bioavailability of dehydroepiandrosterone mediated by nano-encapsulation.

Polymeric nanocarriers, especially nanospheres (NSs) and nanocapsules (NCs), can promote the penetration of their cargo through the skin barrier, towards improved cutaneous bioavailability. Dehydroepiandrosterone (DHEA), an endogenous hormone exhibiting poor aqueous solubility, was shown to be effective in modulating skin-aging processes following topical application. In this study, we designed adequate DHEA preparations, in an attempt to enable local delivery of the active ingredient to the viable skin layers. In addition, the potential efficiency of DHEA NCs on dermal collagen synthesis was evaluated. Cryo-TEM observations and thermal analysis indicated that DHEA was successfully incorporated within a stable NC-based delivery system. Moreover, higher [(3)H]-DHEA levels were recorded in the viable skin layers following different incubation periods of NCs on excised pig skin specimens as compared to DHEA oil solution (free molecule). Furthermore, significantly higher (4-fold) skin flux values were observed for the DHEA NCs as compared to the values elicited by the oil control solution. Finally, collagen synthesis in human skin organ culture, assessed by the incorporation of [(3)H]-proline, was up to 42% higher for DHEA NCs 48h post-topical application than for the untreated specimens. Overall, these results suggest that poly lactic-co-glycolic acid (PLGA)-based NCs have promising potential to be used topically for various skin disorders.

A quantitative evaluation of the molecular binding affinity between a monoclonal antibody conjugated to a nanoparticle and an antigen by surface plasmon resonance.

We have designed a site-specific drug colloidal carrier ultimately for improving pancreatic and lung cancer treatment. It is based on a nanoparticulate drug delivery system that targets tumors overexpressing H-ferritin. A monoclonal antibody, AMB8LK, specifically recognizing H-ferritin was thiolated and conjugated to maleimide-activated polylactide nanoparticles (NPs) resulting in the formation of immunonanoparticles (immunoNPs). The AMB8LK immunoNPs exhibited a mean diameter size of 112+/-20nm and a density of 76 antibody molecules per NP. AMB8LK immunoNPs were evaluated for uptake and binding properties on CAPAN-1 and A-549 cell lines, using confocal microscopy. ImmunoNPs demonstrated specific binding and increased uptake of the desired cells by means of monoclonal antibodies (MAbs), compared to nonconjugated NPs. A lipophilic paclitaxel derivative, paclitaxel palmitate (pcpl), was encapsulated within the various NP formulations, and their cytotoxic effect was evaluated on A-549 cells using MTT assay. Pcpl-loaded AMB8LK immunoNPs showed a significantly increased cytotoxic effect when compared to pcpl solution and pcpl NPs. Surface plasmon resonance (SPR) was used to determine quantitatively the affinity constants of native AMB8LK and AMB8LK immunoNPs to gain insight on the affinity of the MAbs following the conjugation process onto NPs. The results of the association/dissociation and affinity kinetics of the interaction between H-ferritin and native AMB8LK or AMB8LK immunoNPs revealed similar constant values, showing that the conjugation process of the MAb to the NPs did not alter the intrinsic specificity and affinity of the MAb to the antigen. In conclusion, at the cellular level, AMB8LK immunoNPs may carry drugs to desired overexpressing antigen cells with adequate affinity properties, potentially leading to improved drug therapy and reduced systemic adverse effects.

Overcoming the formulation obstacles towards targeted chemotherapy: in vitro and in vivo evaluation of cytotoxic drug loaded immunonanoparticles.

The aim of this study was to design a new one step conjugation of monoclonal antibodies (MAbs) to surface activated pegylated polyester nanoparticles (NPs) and evaluate the pharmacokinetic profile and therapeutic effect of paclitaxel palmitate (pcpl) loaded anti-HER2 immunoNPs in mice as compared to pcpl solution and NPs following IV injection. The density of the antibody conjugated to the NPs was found to be around 35 MAbs/NP (70% coupling efficiency). In vitro cell culture studies showed good binding and uptake results when immunoNPs were incubated with PC-3 and CAPAN-1 cell lines. Both pcpl NPs and immunoNPs showed significant increased t1/2, C(max) and AUC values as compared to the values of pcpl solution in mice. There was no significant difference in the C(max) and AUC values between pcpl NPs and pcpl immunoNPs. However, the immunoNPs concentrated much less in the liver and spleen than NPs. The pharmacokinetic behavior of the immunoNPs was markedly different from the pharmacokinetic profile of the naked MAb showing that the MAb lost its intrinsic molecular pharmacokinetic properties following conjugation to the NPs. The immunoNPs elicited a significant anti-tumor activity as compared to the pcpl solution and NPs, although the tumor growth was not fully inhibited.

Targeting of nanoparticles to the clathrin-mediated endocytic pathway.

Nanoparticles (NPs) are considered attractive carriers for gene therapy and drug delivery owing to their minor toxic effect and their ability to associate and internalize into mammalian cells. In this study, we compared the endocytosis into HeLa cells of NPs exposing either a negative or positive charge on their surface. The exposed charge significantly affected their ability to internalize as well as the cellular endocytosis mechanism utilized. Negatively charged NPs show an inferior rate of endocytosis and do not utilize the clathrin-mediated endocytosis pathway. On the other hand, positively charged NPs internalize rapidly via the clathrin-mediated pathway. When this pathway is blocked, NPs activate a compensatory endocytosis pathway that results in even higher accumulation of NPs. Overall, the addition of a positive charge to NPs may improve their potential as nanoparticulate carriers for drug delivery.