Biomimetic solid lipid nanoparticles for oral bioavailability enhancement of low molecular weight heparin and its lipid conjugates: in vitro and in vivo evaluation
Authors: Govind P Agrawal
Rishi Paliwal
Shivani R Paliwal
Suresh P Vyas
Journal: Molecular pharmaceutics (2011)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: LMWH; lipid conjugates; solid lipid nanoparticles; oral bioavailability; vascular disorders
Affiliations: Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Vishwavidyalaya, Sagar, M.P., India, 470003., Drug Delivery Research Laboratory and ‡Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Vishwavidyalaya, Sagar, M.P., India, 470003

Abstract:  Low molecular weight heparin (LMWH) is an anionic oligosaccharide macromolecule, which is commonly administered via parenteral routes for the treatment of vascular disorders like deep vein thrombosis (DVT) and pulmonary embolism (PE). Oral heparin delivery can tremendously improve the treatment of such disorders but is restricted due to its large size and anionic character. The present investigation describes synthesis of LMWH-lipid conjugates and their encapsulation in phosphatidylcholine stabilized biomimetic solid lipid nanoparticles (SLNs) for LMWH's oral bioavailability enhancement. Briefly, LMWH was conjugated with different saturated lipids of varying chain length (stearic acid, palmitic acid and myristic acid) using carbodiimide chemistry. The conjugation was confirmed with IR and (1)H NMR spectroscopy. The LMWH-lipid conjugate loaded SLNs were characterized for various parameters like shape, size, zeta potential, entrapment efficiency and in vitro release behavior in different simulated GIT pH mediums. The GIT toxicity of LMWH-lipid conjugate loaded SLNs to different tissues of intestinal epithelium was observed using H&amp;E staining followed by microscopic observation at cellular level. The LMWH-lipid conjugate loaded SLNs were found to be safe for oral administration. The plasma concentration of LMWH was estimated using anti-FXa chromogenic assay. A significantly higher bioavailability (p &lt; 0.05) of LMWH was observed using LMWH-lipid conjugates loaded SLNs in comparison to LMWH loaded SLNs and free LMWH. The order of different conjugates in bioavailability enhancement was LMWH-stearic acid &gt; LMWH-palmitic acid &gt; LMWH-myristic acid. This strategy holds promise for future applications of oral delivery of LMWH conjugates in the form of SLNs particularly for the treatment of cardiovascular disease like DVT and PE. 

Retracted: No

PubPeer comments:
 Figure 1.  Transmission electron microphotograph of LMWHu0001lipid conjugate loaded SLNs. Particles were spherical in shape with uniform distribution throughout the dispersion, and the observations were made at least three times for each formulation . ![file] Figure 1 from [Paliwal et al (2009)] .  TEM photographs of different MTX-loaded SLNs formulations (stabilized by 1% (w w) soya lecithin). (A) MTX-SA; (B) MTX-MS; (C) MTX-TS; **(D) MTX-CA** . ![file] One of these images is a modified version of the other, but which? , 
 Corrected, [5 May 2020] .  In the original publication, we reported Figure 1 as a transmission electron microphotograph (TEM) of low molecular weight heparin (LMWH)-lipid conjugate loaded solid lipid nanoparticles (SLNs). The image was inadvertently wrongly provided. The corrected TEM image is appended below. This correction does not affect the main conclusion of the manuscript. We sincerely apologize for this unfortunate incidence and inconvenience caused to the readers due to this error. ![file] There is no indication of how the original error occurred, i.e. how an image was formed that is clearly a modified version of an image used in a different paper. The correction may not  affect the main conclusion of the manuscript but it does affect our confidence in the authors reliability. ,