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Liposomal Dry Powders As Aerosols for Pulmonary Delivery of Proteins

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Liposomal Dry Powders As Aerosols for Pulmonary Delivery of Proteins AAPS PharmSciTech 2005; 6 (4) Article 80 (http://www.aapspharmscitech.org). Liposomal Dry Powders as Aerosols for Pulmonary Delivery of Proteins Submitted: January 22, 2005; Accepted: September 13, 2005; Published: December 21, 2005 Dongmei Lu1 and Anthony J. Hickey1 1 School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 ABSTRACT of acceptable pulmonary bioavailability led to interest in their presentation for absorption via the lungs. The purpose of this research was to develop liposomal dry powder aerosols for protein delivery. The delivery of stable Liposomes are promising vehicles for pulmonary drug protein formulations is essential for protein subunit vaccine delivery owing to their capacity to target drug to cells, such delivery, which requires local delivery to macrophages in the as macrophages, and to alter pharmacokinetics of drugs.2,3 lungs. β-Glucuronidase (GUS) was used as a model protein They also provide sustained release, prevent local irritation, to evaluate dry powder liposomes as inhaled delivery vehi- increase drug potency, reduce toxicity, and uniformly cles. Dimyristoyl phosphatylcholine:cholesterol (7:3) was deposit active drugs locally.4,5 selected as the liposome composition. The lyophilization 6 of liposomes, micronization of the powders, aerosoliza- Some proteins and enzymes, such as glutathione, super- 7 8 tion using a dry powder inhaler (DPI), and in vitro aero- oxide dismutase, and catalase, have been encapsulated by dynamic fine particle fraction upon collection in a twin- liposomes to improve their pulmonary delivery, and most stage liquid impinger were evaluated. After lyophilization of them were administered intratracheally into the respira- 2 and jet-milling, the total amount of GUS and its activity, tory tract in liquid-based liposomes. Nebulizers have been 9,10 representing encapsulation efficiency and stability, were used extensively for the delivery of liposomes. However, evaluated. The GUS amount and activity were measured delivery of liposomes by nebulization may be hampered by and compared with freshly-prepared liposomes in the pres- long-term instability problems that lead liposome disper- ence of mannitol, 43% of initial GUS amount, 29% of sions to undergo physiochemical changes resulting in 11 GUS activity after lyophilization and 36% of GUS amount, leakage of the encapsulated drug. Among formulations 22% of activity after micronization were obtained. Emit- employed for drug delivery to the lungs, dry powders stand ted doses from dry powder inhaler were 53%, 58%, 66%, out because of the stability of drugs and formulations. and 73% for liposome powder:mannitol carrier ratios of Dry powder delivery is an important inhalation technol- 1:0, 1:4, 1:9, and 1:19. Fifteen percent of the liposome ogy. Dry powder products may consist of drug alone or particles were less than 6.4 μm in aerodynamic diameter. blended with excipient that acts as a carrier for delivery to 12 The results demonstrate that milled liposome powders the lungs. Freeze-dried liposomes have been prepared for 13 containing protein molecules can be aerosolized effectively aerosol delivery to improve liposome stability. Another at a fixed flow rate. Influences of different cryoprotectants method of preparing dry powder liposomes is by spray- 14 15 on lyophilization of protein liposome formulations are re- drying. Some small molecules, such as Budsonide and 16 ported. The feasibility of using liposomal dry powder Ketotifen, have been prepared in freeze-dried liposomes aerosols for protein delivery has been demonstrated but to form a dry powder dispersion for inhalation. These in- further optimization is required in the context of specific vestigations demonstrated the possibility of delivering lipo- therapeutic proteins. somally entrapped small molecules to terminal bronchioles in therapeutic doses and offered the exciting possibility of aerosol delivery as dry powder formulations. KEYWORDS: protein, liposome, lyophilization, dry pow- ders, aerosol, pulmonary deliveryR Few studies have been performed to evaluate whether thera- peutic proteins in liposomes can be aerosolized into the respi- ratory tract in dry powder formulations. Superoxide dismutase INTRODUCTION was encapsulated in the spray-dried liposomes to evaluate 14 Drug delivery via the lungs received considerable attention respirable properties. In our present studies, a model pro- throughout the 1990s.1 Difficulties associated with the de- tein was used to evaluate both the feasibility of delivering livery of peptides and proteins, coupled with the likelihood dry powder liposome formulations for protein and, more importantly, whether the process of lyophilization could be used to prepare dry powders suitable for pulmonary delivery. Corresponding Author: Anthony J. Hickey, Kerr Hall 1311, School of Pharmacy, CB#7360, University of North The majority of studies describing pulmonary delivery of Carolina at Chapel Hill, Chapel Hill, NC 27599. Tel: (919) proteins and peptides have focused on systemic delivery of 962-0223; Fax: (919) 966-0197; E-mail: [email protected] drugs.17-21 The present studies are concerned with the E641 AAPS PharmSciTech 2005; 6 (4) Article 80 (http://www.aapspharmscitech.org). delivery of proteins for local activity, specifically the deliv- natant to encapsulated protein in liposomes was less than 2%. ery of subunit vaccines to elicit cell-mediated responses for The freshly prepared liposomes were subjected to quasi- tuberculosis prevention.22 Many of these proteins are in lim- elastic, dynamic light scattering particle size analysis (NIC- ited supply and a formulation strategy requires an approach OMP Submicron Particle Sizer autodilute, model 370, Santa validated using model proteins. The enzyme, β-glucuronidase Barbara, CA). A volume of 600 μL 0.1% Triton X-100 was (GUS), was evaluated as a model protein in preliminary added into 400 μL freshly prepared liposomes to disrupt the studies of liposome formulation, lyophilization, microniza- liposome vehicles for protein quantification and activity assay. tion, and aerodynamic size distributions. The specific aims of the study are to (1) prepare liposomes containing the model protein, (2) adopt methods for lyophilization and milling that Liposome Lyophilization result in fine particles suitable for inhalation, and (3) to char- Liposome suspensions were frozen in dry ice-acetone. The acterize the powder in terms of protein structure or activity liposomes were lyophilized (Labconco Freeze Dry System, before and after the various processes and aerosolization. Freezone 6, Kansas City, Missouri) at −45°C for 48 hours. MATERIALS AND METHODS Milling Materials One gram of the lyophilized liposomes was micronized (Trost Dipalmitoyl phosphatidylcholine (DPPC), dimyristoyl phos- GEM-T jet mill, Plastomer Products, Newton, NJ) with dry phatidylcholine (DMPC), dioleoyl phosphatidylcholine nitrogen gas (60 and 40 pounds per square inch gauge [psig] (DOPC), Dioleoyl trimethylammonium propane (DOTAP), of pusher and grinder pressure, respectively). The powders dioleoyl phosphatidylglycerol (DOPG), and cholesterol (CH) were collected from cyclone and jar. The micronized parti- were purchased from Avanti Polar Lipids, Inc (Alabaster, cles were stored in a desiccator containing silica gel under AL). D-mannitol, sucrose, sodium phosphate monobasic, vacuum at room temperature (20°C-21°C) until required. HEPES, ammoniumferrothiocyanate, phenolphthalein glu- Powders were stored for a maximum of 2 days before curonic acid, and GUS from bovine liver (type B-1) were characterization and further assay were performed. purchased from Sigma (St Louis, MO). Povidone (polyvinyl- pyrrolidone [PVP], Mw 40 000) was from Spectrum (Gardena, CA). PAGE gel (Bio-rad ready gels, 7.5% Tris-HCl) and pro- Characterization of Liposomes tein quantification kit DC protein assay package were from Lyophilized liposomes, before and after jet-milling, were Bio-Rad(Hercules,CA).Allmaterialswereusedasreceived. characterized by Scanning Electron Microscopy (SEM, model 6300, JEOL, Peabody, NY). The stubs were coated with gold-palladium alloy (150-250Å) using a sputter coater Methods (Polaron 5200, Structure Probe Supplies, West Chester, PA). Liposome Preparation The coater was operated at 2.2k V, 20 mV, 0.1 torr (argon) Different components of liposomes were prepared by for 90 seconds. An accelerating voltage of 15 kV was used. dehydration-rehydration and then freezing- thawing meth- ods. Different fatty acid chain length (DOPC, DMPC, Dry Liposome Reconstitution DPPC) and charged lipids (DOPG and DOTAP) together with cholesterol were screened for encapsulation effi- Quantities of lyophilized or jet-milled liposomes were re- ciency. DOPC- CH (7:3), DOPC-CH-DOTAP (7:2:1, 7:1:2), constituted in 20 mM phosphate buffer (pH 7.4) to original DOPC-CH-DOPG (7:2:1), DMPC-CH (7:3) and DPPC-CH concentrations in preparation. Samples were vortexed for (7:3) were used as lipid components. Lipids were dissolved 2 seconds and centrifuged twice to separate the free drug at in chloroform, and the solvent was evaporated by nitrogen. g = 25 000, 10°C for 30 minutes. A volume of 1000 µl of The lipid films were put into vacuum desiccators in the 0.1% Triton X-100 was added into the lipid pellets to disrupt presence of dry silica gel for 2 hours to remove chloroform. lipid vesicles for protein quantification and activity assay. The dry lipid films were hydrated in 20 mM sodium phos- phate buffer (pH 7.4), containing 25 mM lipids, 250 mM
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