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1.  Optimization of experimental parameters for the production of LMWH-loaded polymeric microspheres 
The present study reports on the production of low molecular weight heparin (LMWH) loaded polymeric microspheres for delivery via the oral route. The microspheres were prepared by the spray-drying technique using Eudragit® as the polymer. The objective of this study was to examine extensively the influence of formulation and process variables on the characteristics of the microspheres prepared. The effects of various experimental parameters such as polymer concentration, inlet temperature, and liquid feed flow rate on particle morphology, particle dimensions, and production yields were evaluated by means of experimental factorial designs. Electron microscopy, moisture content analysis, and fractal dimensional analysis were employed to characterize the microspheres. The inlet temperature and polymer concentration had the greatest effects on the production yield. Results showed that the polymer concentration affected the dimensions of the microspheres. Drug-loaded microspheres were spherical in shape and had a smooth surface with sizes ranging between 19–60 μm. Production yields were above 50% under most of the operating parameters studied. The selection of appropriate parameters yielded spray-dried microparticles characterized by smooth morphology and narrow dimensional distribution.
PMCID: PMC2761187  PMID: 19920892
spray drying; LMWH; DOE; fractal; microspheres
2.  The quest for non-invasive delivery of bioactive macromolecules: A focus on heparins 
The development of a non-invasive drug delivery system for unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) has been the elusive goal of several research groups since the initial discovery of this glycosaminogylcan by McLean in 1916. After a brief update on current parenteral formulations of UFH and LMWHs, this review revisits past and current strategies intended to identify alternative routes of administration (e.g. oral, sublingual, rectal, nasal, pulmonary and transdermal). The following strategies have been used to improve the bioavailability of this bioactive macromolecule by various routes: (i) enhancement in cell-membrane permeabilization, (ii) modification of the tight-junctions, (iii) increase in lipophilicity and (iv) protection against acidic pH of the stomach. Regardless of the route of administration, a simplified unifying principle for successful non-invasive macromolecular drug delivery may be: “to reversibly overcome the biological, biophysical and biochemical barriers and to safely and efficiently improve the in vivo spatial and temporal control of the drug in order to achieve a clinically acceptable therapeutic advantage”. Future macromolecular drug delivery research should embrace a more systemic approach taking into account recent advances in genomics/proteomics and nanotechnology.
doi:10.1016/j.jconrel.2006.04.008
PMCID: PMC1539865  PMID: 16777255
Alternative routes; Bioactive macromolecule; Drug delivery; Non-invasive; Heparin
3.  Modulation of gastrointestinal permeability of low-molecular-weight heparin by l-arginine: in-vivo and in-vitro evaluation 
l-Arginine is the principal physiological precursor of nitric oxide (NO, a key neurotransmitter) that plays a versatile role in the physiology of the gastrointestinal tract. In this study, the efficacy of l-arginine in enhancing intestinal absorption of ardeparin, a low-molecular-weight heparin (LMWH) was investigated in Caco-2 cell monolayers and a rat model. Regional permeability studies using rat intestine were performed using a modified Ussing chamber. Cell viability in the presence of various concentrations of enhancer was determined by MTT assay. Furthermore, the eventual mucosal epithelial damage was histologically evaluated. LMWH formulated with l-arginine was administered orally to mate Sprague-Dawley rats and the absorption of LMWH was determined by measuring plasma anti-factor Xa activity. Higher ardeparin in-vitro permeability (~3 fold) compared with control was observed in the presence of 2% l-arginine. Regional permeability studies indicated predominant absorption in the colon region. Cell viability studies showed no significant cytotoxicity below 0.8% l-arginine. The oral bioavailability of ardeparin formulated with l-arginine (250 mg kg−1) was increased by ~2 fold compared with control. The formulation was well tolerated by the rats and no abnormal histopathological findings were observed in intestinal tissues of rats exposed to l-arginine. These results suggest that l-arginine may be useful in enhancing the intestinal absorption of LMWHs.
doi:10.1211/jpp.58.5.0003
PMCID: PMC1557380  PMID: 16640827
4.  Zonula occludens toxin synthetic peptide derivative AT1002 enhances in vitro and in vivo intestinal absorption of low molecular weight heparin 
Journal of drug targeting  2006;14(5):321-329.
Zonula occludens toxin (Zot) is an enterotoxin obtained from the bacterium vibrio cholerae that has been shown to reversibly and safely open the tight junctions and enhance paracellular transport. AT1002 is a novel synthetic hexapeptide derived from Zot. The hypothesis to be tested in this study is that AT1002 enhances the oral absorption of ardeparin, a low molecular weight heparin (LMWH). To test this hypothesis, drug transport through Caco-2 cell monolayers was monitored in the presence and absence of AT1002. Regional permeability studies using rat intestine were performed. Cell viability in the presence of various concentrations of enhancer was determined. The absorption of ardeparin after oral administration in rats was measured by anti-factor Xa assay. Furthermore, the eventual mucosal and epithelial damage was histologically evaluated. Higher ardeparin permeability (~2-fold) compared to control was observed in the presence of 0.025% of AT1002. Regional permeability studies revealed that the permeability of ardeparin across the duodenal membrane was improved by the AT1002. Cell viability studies showed no significant cytotoxicity below 0.0028% of AT1002. In the presence of 100 μg/kg of AT1002, ardeparin oral bioavailability was significantly increased (Frelative/s.c ~ 20.5%). Furthermore, AT1002 at a dose of 100 μg/kg did not induce any observable morphological damage on gastrointestinal (GI) tissues in vivo. These in vivo and in vitro results suggest that the co-administration of LMWH with AT1002 may be a useful delivery strategy to increase its permeability and hence oral absorption.
doi:10.1080/10611860600613316
PMCID: PMC1994914  PMID: 16882552
AT1002; low molecular weight heparin; enhancer; oral delivery; zonula occludens toxin
5.  Oral delivery of low-molecular-weight heparin using sodium caprate as absorption enhancer reaches therapeutic levels 
Journal of drug targeting  2005;13(10):573-583.
The primary objective of this study was to evaluate sodium caprate as an oral penetration enhancer for low molecular weight heparin (LMWH), ardeparin. In vitro studies using Caco-2 cell monolayer indicated that 0.0625% of sodium caprate gave approximately 2-fold enhancement of ardeparin compared to negative control with almost 100% cell survival as evaluated by MTT cytotoxicity assay. In vivo studies in rats with ardeparin (1200 IU/kg) and sodium caprate (100 mg/kg) led to a relative bioavailability of 27% with plasma anti-factor Xa levels within the therapeutic range (> 0.2 IU/ml). Moreover, under these conditions, histological examination provided evidence that there was no damage to the gastrointestinal wall. Regional permeability studies using rat intestine indicated the colon as the region of maximum permeation. These results suggest that, at the dose administered, sodium caprate acts as a relatively safe and efficient absorption enhancer in the quest for alternatives for the oral delivery of LMWH.
doi:10.1080/10611860500471906
PMCID: PMC1993550  PMID: 16390818
Sodium caprate; low molecular weight heparin; Caco-2 cell monolayer; absorption enhancer; ardeparin; oral absorption
6.  Evaluation of the Oral Bioavailability of Low Molecular Weight Heparin Formulated With Glycyrrhetinic Acid as Permeation Enhancer 
Drug development research  2006;67(2):166-174.
Low molecular weight heparin (LMWH) is the agent of choice for anticoagulant therapy and prophylaxis of thrombosis and coronary syndromes. However, its therapeutic use is limited due to poor oral bioavailability. The aim of this study was to investigate the oral delivery of LMWH, ardeparin formulated with 18-β glycyrrhetinic acid (GA), as an alternative to currently used subcutaneous (sc) delivery. Drug transport through Caco-2 cell monolayers was monitored in the presence and absence of GA by scintillation counting and transepithelial electrical resistance. Regional permeability studies using rat intestine were performed using a modified Ussing chamber. Cell viability in the presence of various concentrations of enhancer was determined by MTT assay. The absorption of ardeparin after oral administration in rats was measured by an anti-factor Xa assay. Furthermore, the eventual mucosal epithelial damage was histologically evaluated. Higher ardeparin permeability (~7-fold) compared to control was observed in the presence of 0.02 % GA. Regional permeability studies indicated predominant absorption in the duodenal segment. Cell viability studies showed no significant cytotoxicity below 0.01 % GA. Ardeparin oral bioavailability was significantly increased (Frelative/S.C. = 13.3%) without causing any damage to the intestinal tissues. GA enhanced the oral absorption of ardeparin both in vitro and in vivo. The oral formulation of ardeparin with GA could be absorbed in the intestine. These results suggest that GA may be used as an absorption enhancer for the oral delivery of LMWH.
doi:10.1002/ddr.20087
PMCID: PMC1948842  PMID: 17710191
glycyrrhetinic acid; LMWH; Caco-2 cells; absorption enhancer; oral delivery

Results 1-6 (6)