Inhalable lactose-based dry powder formulations of low molecular weight heparin.
BACKGROUND
Currently low molecular weight heparin (LMWH) is administered as subcutaneous injection. This study sought to investigate the feasibility of LMWH as an inhalable dry powder (DPI) formulation and evaluate the interaction of the drug with lactose when used as a carrier. The study also compares the extent of pulmonary absorption of LMWH administered as a dry powder with that administered as an aerosolized aqueous solution.


METHODS
The formulations were prepared by mixing LMWH in an aqueous solution of lactose followed by lyophilization of the resulting solution. The lyophilized preparation was then ground and sieved. Physical characterization of the formulations was performed by Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), particle size analysis, and determination of aerodynamic diameter. For in vivo studies, formulations were administered to anesthetized rats, and drug absorption was monitored by measuring plasma antifactor Xa activity.


CONCLUSIONS
In the FTIR scan, all characteristic peaks of lactose and LMWH were observed, suggesting that there was no strong interaction between lactose and LMWH. Although the aerodynamic diameter of the formulation (DPI-2) that was sieved through 170- and 230-mesh screens was similar to that of the formulation (DPI-1) sieved through 120- and 170-mesh screens, the particle sizes of the two formulations were significantly different. Dry powder formulations of LMWH were better absorbed compared to an inhalable solution of LMWH. One of the dry powder formulations (DPI-2) produced an almost 1.5-fold increase in the relative bioavailability (41.6%) compared to the liquid formulation of LMWH (32.5%). Overall, the data presented here suggest that lactose does not adversely affect the physical-chemical characteristics of the drug, and that lactose can be used as a carrier for pulmonary delivery of LMWH.
Bai
Shuhua
S
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, TX 79106, USA.
Gupta
Vivek
V
Ahsan
Fakhrul
F
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005079:Excipients / Q000737:chemistry*; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007785:Lactose / Q000737:chemistry*; D008297:Male; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
D000336:Aerosols; D000925:Anticoagulants; D005079:Excipients; D006495:Heparin, Low-Molecular-Weight; D011208:Powders; D007785:Lactose