Now showing 1 - 6 of 6
  • Publication
    Safety concerns over the use of intestinal permeation enhancers: A mini-review
    Intestinal permeation enhancers (PEs) are key components in ∼12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo- and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.
      291Scopus© Citations 86
  • Publication
    Evaluation of Sucrose Laurate as an Intestinal Permeation Enhancer for Macromolecules: Ex Vivo and In Vivo Studies
    Oral delivery of macromolecules requires permeation enhancers (PEs) adaptable to formulation. Sucrose laurate (SL) (D1216), a food grade surfactant, was assessed in Caco-2 monolayers, isolated rat intestinal tissue mucosae, and rat intestinal instillations. Accordingly, 1 mM SL increased the apparent permeability coefficient (Papp) of [14C]-mannitol and reduced transepithelial electrical resistance (TEER) across monolayers. It altered expression of the tight junction protein, ZO-1, increased plasma membrane potential, and decreased mitochondrial membrane potential in Caco-2 cells. The concentrations that increased flux were of the same order as those that induced cytotoxicity. In rat colonic tissue mucosae, the same patterns emerged in respect to the concentration-dependent increases in paracellular marker fluxes and TEER reductions with 5 mM being the key concentration. While the histology revealed some perturbation, ion transport capacity was retained. In rat jejunal and colonic instillations, 50 and 100 mM SL co-administered with insulin induced blood glucose reductions and achieved relative bioavailability values of 2.4% and 8.9%, respectively, on a par with the gold standard PE, sodium caprate (C10). The histology of the intestinal loops revealed little damage. In conclusion, SL is a candidate PE with high potential for emulsion-based systems. The primary action is plasma membrane perturbation, leading to tight junction openings and a predominant paracellular flux.
      146Scopus© Citations 26
  • Publication
    Physicochemical, pharmacokinetic and pharmacodynamic analyses of amphiphilic cyclodextrin-based nanoparticles designed to enhance intestinal delivery of insulin
    Due to excellent efficacy, low toxicity, and well-defined selectivity, development of new injectable peptides is increasing. However, the translation of these drugs into products for effective oral delivery has been restricted due to poor oral bioavailability. Nanoparticle (NP) formulations have potential to overcome the barriers to oral peptide delivery through protecting the payload and increasing bioavailability. This study describes the rational design, optimization and evaluation of a cyclodextrin-based NP entrapping insulin glulisine for intestinal administration. A cationic amphiphilic cyclodextrin (click propyl-amine cyclodextrin (CD)) was selected as the primary complexing agent for NP development. Following NP synthesis, in vitro characterization was performed. The insulin glulisine NPs exhibited an average size of 109 ± 9 nm, low polydispersity index (0.272) negative zeta potential (−25 ± 3 mV), high association efficiency (71.4 ± 3.37%) and an insulin loading of 10.2%. In addition, the NPs exhibited colloidal stability in intestinal-biorelevant media (SIF, supplemented-SIF 1% (w/v) and FaSSIF-V2) for up to 4 h. Proteolysis studies indicated that the NPs conferred protection to the entrapped insulin relative to free insulin. In vivo rat jejunal instillation studies demonstrated that the NPs mediated systemic insulin absorption, accompanied by a decrease in blood glucose levels. The relative bioavailability of the instilled insulin (50 IU/kg) from the NP was 5.5% compared to subcutaneous administration of insulin solution (1 IU/kg). The pharmacodynamic and pharmacokinetic data indicate that this cyclodextrin-based formulation may have potential for further research as an oral insulin dosage form.
      578Scopus© Citations 43
  • Publication
    Labrasol® is an efficacious intestinal permeation enhancer across rat intestine: Ex vivo and in vivo rat studies
    Labrasol® ALF (Labrasol®), is a non-ionic surfactant excipient primarily used as a solubilising agent. It was investigated here as an intestinal permeation enhancer in isolated rat colonic mucosae in Ussing chamber and in rat in situ intestinal instillations. Labrasol® comprises mono-, di- and triglycerides and mono- and di- fatty acid esters of polyethylene glycol (PEG)-8 and free PEG-8, with caprylic (C8)- and capric acid (C10) as the main fatty acids. Source components of Labrasol® as well as Labrasol® modified with either C8 or C10 as the sole fatty acid components were also tested to determine which element of Labrasol® was responsible for its permeability-enhancing properties. Labrasol® (4, 8 mg/ml) enhanced the transport of the paracellular markers, [14C] mannitol, FITC-dextran 4000, and FITC-insulin across colonic mucosae. The enhancement was non-damaging, transient, and molecular weight-dependent. The PEG ester fraction of Labrasol® also had enhancing properties. When insulin was administered with Labrasol® in instillations, it had a relative bioavailability of 7% in jejunum and 12% in colon. C8- and C10 versions of Labrasol® and the PEG ester fraction also induced similar bioavailability values in jejunal instillations: 6, 5 and 7% respectively. Inhibition of lipases in instillations did not reduce the efficacy of Labrasol®, suggesting that its mechanism as a PE is not simply due to liberated medium chain fatty acids. Labrasol® acts as an efficacious intestinal permeation enhancer and has potential for use in oral formulations of macromolecules and BCS Class III molecules.
      480Scopus© Citations 59
  • Publication
    An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations when Combined with a Permeation Enhancer
    The use of nanocarriers is being researched to achieve oral peptide delivery. Insulin-associated anionic polyelectrolyte nanoparticle complexes (PECs) were formed that comprised hyaluronic acid and chitosan in an optimum mass mixing ratio of 5:1 (MR 5), followed by coating with a pH-dependent polymer. Free insulin was separated from PECs by size exclusion chromatography and then measured by HPLC. The association efficiency of insulin in PECs was >95% and the loading was ~83 µg/mg particles. Dynamic light scattering and nanoparticle tracking analysis of PECs revealed low polydispersity, a negative zeta potential range of −40 to −50 mV, and a diameter range of 95–200 nm. Dissolution studies in simulated small intestinal fluid (FaSSIF-V2) revealed that the PECs were colloidally stable. PECs that were coated with Eudragit® L-100 delayed insulin release in FaSSIF-V2 and protected insulin against pancreatin attack more than uncoated PECs. Uncoated anionic PECs interacted weakly with mucin in vitro and were non-cytotoxic to Caco-2 cells. The coated and uncoated PECs, both concentrated further by ultrafiltration, permitted dosing of 50 IU/kg in rat jejunal instillations, but they failed to reduce plasma glucose or deliver insulin to the blood. When ad-mixed with the permeation enhancer (PE), sucrose laurate (100 mM), the physicochemical parameters of coated PECs were relatively unchanged, however blood glucose was reduced by 70%. In conclusion, the use of a PE allowed for the PEC-released bioactive insulin to permeate the jejunum. This has implications for the design of orally delivered particles that can release the payload when formulated with enhancers.
      125Scopus© Citations 14
  • Publication
    Effects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosae
    Surfactant-based intestinal permeation enhancers (PEs) are constituents of several oral macromolecule formulations in clinical trials. This study examined the interaction of a test panel of surfactant-based-PEs with isolated rat colonic mucosae mounted in Ussing chambers in an attempt to determine if increases in transepithelial permeability can be separated from induction of mucosal perturbation. The aim was to establish assess if increases in permeability (i) intestinal permeability (the apparent permeability coefficient (Papp) of [14C]-mannitol), (ii) epithelial histology, and (iii) short-circuit current (ΔIsc) responses to a cholinomimetic (carbachol, CCh). Enhancement ratio increases for Papp values followed the order: C10 > C9 = C11:1 > a bile salt blend > sodium choleate > sucrose laurate > Labrasol® >C12E8 > C12 > Cremophor® A25 > C7 > sucrose stearate > Kolliphor® HS15 > Kolliphor® TPGS. Exposures that increased the Papp by ≥2-fold over 120 min were accompanied by histological damage in 94% of tissues, and by a decreased ΔIsc response to CCh of 83%. A degree of separation between the increased Papp of [14C]-mannitol, histological damage, and diminution of the ΔIsc response to CCh was observed at selected PE concentrations (e.g. Labrasol® at 2 mg/mL). Overall, this surfactant-based PE selection caused transcellular perturbation at similar concentrations to those that enhanced permeability.
      583Scopus© Citations 28