Oral delivery of low molecular weight heparin microspheres prepared using biodegradable polymer matrix system

Abstract

Parenteral route is preferred for low molecular weight heparin (LMWH) due to poor oral bioavailability. Biodegradable formulation components were evaluated for possible interactions between the physical mixtures using differential scanning calorimetry. LMWH and an absorption enhancer papain were encapsulated in bovine serum albumin matrix and four formulations were spray-dried (MS.1, MS.2, MS.3, MS.4). Formulations were evaluated for product yield, particle size, particle charge and encapsulation efficiency. In vitro release assessed in pH 7.2 phosphate buffer saline (PBS) revealed a burst release effect (60%) for all the formulations except MS.1. In vivo studies performed in male Sprague Dawley rats showed an enhancement in drug absorption for the MS.2 and MS.3 formulations because of papain action on paracellular tight junctions. A significant increase in LMWH oral bioavailability was demonstrated by MS.3 (21%), among the formulations encapsulated with papain.

Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres

“…After this discovery, researchers began engineering microspheres (MSs) to deliver drugs with poor water solubility (8)(9)(10), poor gastrointestinal permeability (11), or poor oral bioavailability (8,9,(12)(13)(14)(15) to the small intestine. MS-based oral drug delivery systems (ODDSs) can be made from biodegradable polymers (12,(16)(17)(18), nondegradable polymers (19)(20)(21), and polysaccharides (22,23) and can be engineered to carry polypeptides (18,24,25) and other molecules (26,27).…”

Passive targeting and lung tolerability of enoxaparin microspheres for a sustained antithrombotic activity in rats

“…Unfortunately, Clexane Õ suffers from short half-life (4.5 h) and general distribution of the drug to all body parts, resulting in the need for daily parenteral administration of large doses with increased risk of hemorrhage especially with long-term LMWH usage. Hence, it is desirable to modify the current treatment approach (Lanke et al, 2009;Bai & Ahsan, 2010).…”

Low molecular weight heparins for current and future uses: approaches for micro- and nano-particulate delivery

“…Common techniques, such as HPLC, ion pair, ion exchange, exclusion chromatography (using ultraviolet (UV)-visible and refractive index detectors) and capillary electrophoresis have all been reported to be unsuccessful in quantification of LMWHs (Oliveira et al, 2011). The most commonly employed methods are the nephelometric method (Meissner et al, 2007;Oliveira et al, 2011), Azure colorimetric method (Sun et al, 2008;) and biological quantification of antifactor Xa activity using chromogenic assay kit (Lanke et al, 2009). Nephelometric method is based on the detection of turbidity caused by water-insoluble complex between the quaternary ammonium groups of cetylpyridinium chloride and the negatively charged sulfated groups of LMWH.…”

“…No effect of the polymers on the tight junction could be detected and no particle translocation across the Peyer's patches was expected due to the large size of the coacervates, which might explain the low values of bioavailabilities obtained. Co-encapsulation of an absorption enhancer (papain) with LMWH into albumin microspheres followed by enteric coating with Eudragit L100-55 and polyethylene glycol 8000 using spray drying was studied for oral delivery of LMWH (Lanke et al, 2009). The spray dried microspheres were all around 5 mm in size and possessed high encapsulation efficiencies (66-78%).…”