Thromboembolism plays a major role in the pathogenesis of cardiovascular diseases. Low molecular weight heparins (LMWHs) are agents of choice for the prevention. Generally, LMWHs and biotechnology drugs present a poor oral bioavailability. Pulmonary delivery is the most promising route of administration for these agents. However, drug disposition into the lung following inhalation is limited by factors such as, formulation aerodynamics, mucociliary clearance, absorption mechanism, tissue sequestration. Therefore, current delivery methods of LMWHs (e.g. subcutaneous injection, s.c.) are invasive, present some hazards (e.g. pain/bleeding) and are not patient compliant. Moreover, it is now well-established that a circadian rhythm exists in these diseases. One approach to overcome the foregoing problems is to develop drug containing large porous microparticles (LPM) with different rate/time-release for pulmonary delivery. Using biodegradable and nonbiodegradable polymers, and three heparins (3,000, 6,000 and 17.000MW), we have preformulated heparin containing LPM with different release rates. Our hypothesis is that formulation of LMWHs containing LPM, which can be administered by pulmonary route can more efficiently deliver the required daily preventive dose of anticoagulant with less side effects than s.c. injection. The rationale for this hypothesis is based on the concept that heparin-LPM could avoid rapid clearance by macrophages and enhance pulmonary drug delivery. Based on this hypothesis, we propose two Specific Aims: 1) evaluate the stability and aerodynamics of heparin containing LPM, and 2) evaluate the bioavailability and bioactivity of the heparin containing LPM by pulmonary route.
In Aim#1, we will assess particle stability, and aerodynamics in a cascade impactor to optimize formulation variables.
In Aim#2, we will use three strategies to enhance LMWHs bioavailability in rat lungs: (i) LPM to reduce macrophage uptake, (ii) mucoadhesive polymer to reduce mucociliary clearance, and (iii) absorption enhancer. We will also perform histological, bleeding and cytotoxicity studies for safety estimation. This grant is a focused plan that will contribute to the identification of the first time-dependent heparin delivery system for improved pharmacotherapy of thrombosis via the lung.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GDD (01))
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas Tech University
Schools of Pharmacy
United States
Zip Code
Youan, Bi-Botti C (2010) Chronopharmaceutical drug delivery systems: Hurdles, hype or hope? Adv Drug Deliv Rev 62:898-903
Motlekar, Nusrat A; Srivenugopal, Kalkunte S; Wachtel, Mitchell S et al. (2006) Evaluation of the Oral Bioavailability of Low Molecular Weight Heparin Formulated With Glycyrrhetinic Acid as Permeation Enhancer. Drug Dev Res 67:166-174
Motlekar, Nusrat A; Youan, Bi-Botti C (2006) The quest for non-invasive delivery of bioactive macromolecules: a focus on heparins. J Control Release 113:91-101
Motlekar, Nusrat A; Fasano, Alessio; Wachtel, Mitchell S et al. (2006) Zonula occludens toxin synthetic peptide derivative AT1002 enhances in vitro and in vivo intestinal absorption of low molecular weight heparin. J Drug Target 14:321-9
Motlekar, Nusrat Abbas; Srivenugopal, Kalkunte Srirangachar; Wachtel, Mitchell S et al. (2006) Modulation of gastrointestinal permeability of low-molecular-weight heparin by L-arginine: in-vivo and in-vitro evaluation. J Pharm Pharmacol 58:591-8
Motlekar, Nusrat A; Srivenugopal, Kalkunte S; Wachtel, Mitchell S et al. (2005) Oral delivery of low-molecular-weight heparin using sodium caprate as absorption enhancer reaches therapeutic levels. J Drug Target 13:573-83