Delivery of therapeutic levels of heparin and low-molecular-weight heparin through a pulmonary route

Abstract

Although heparin and low-molecular-weight heparins (LMWH) have been widely used clinically as anticoagulants, their broader use has been limited by the lack of noninvasive delivery methods for this class of molecules. In this study, we demonstrate an efficient, rapid, and reproducible delivery system for heparin through the lungs that is not confined to particles of a certain geometric or aerodynamic diameter. Importantly, blood levels after intrapulmonary administration of either heparin or LMWH were comparable to that of s.c. administration but are characterized by a more rapid onset of action (t 1/2 ‫؍‬ 40 min vs. 2.5 h, respectively). Furthermore, we show in animal models, that inhaled heparin species efficiently inhibit diseases such as thrombosis and emphysema, and that the repetitive inhalation of formulated LMWH results in no observable toxicity from the delivery of reproducible systemic levels of heparin or LMWH.

Synthesis and Evaluation of Pegylated Dendrimeric Nanocarrier for Pulmonary Delivery of Low Molecular Weight Heparin

“…However, the use of LMWHs on an outpatient basis has been limited because of the requirement of daily subcutaneous injections. Consequently, attempts have been made to deliver LMWHs via noninvasive routes, including the nasal and pulmonary routes (9,(12)(13)(14)(15)(16)(17). Previously, we showed that, similar to DNA-dendrimer complexation, a full-generation cationic PAMAM dendrimer interacts with electronegative functional groups of LMWHs and increases the pulmonary absorption of the drug (17).…”

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

“…Pulmonary administration of LMWH-loaded microparticles (MPs) containing 60% dipalmitoyl phosphatidylcholine prepared by spray drying or mechanical grinding produced therapeutic levels of the drug (40.2 IU/ml) and a very rapid onset of action compared to SC route (Qi et al, 2004). Differently sized particles with geometric diameters of 20-80 mm indicated that absorption and bioavailability were particle size independent in this range.…”

Influence of chemical and structural features of low molecular weight heparins (LMWHs) on skin penetration

“…The poor intestinal absorption together with the degradation of heparins both in liver and in gastrointestinal tract make the oral administration not feasible (Qi et al, 2004). Transdermal delivery may represent a valid alternative, even if LMWHs diffusivity through the skin is limited by large M w , hydrophilicity and negative charge (Gomaa et al, 2012).…”