The Influence of Liposomal Encapsulation on Sodium Cromoglycate Pharmacokinetics in Man
ABSTRACT The pharmacokinetics of pulmonary-administered sodium cromoglycate (SCG) has been studied in five healthy volunteers. SCG, 20 mg, was inhaled as a solution and encapsulated in dipalmitoyl phosphatidylcholine/cholesterol (1:1) liposomes. Liposomal SCG produced detectable drug levels in plasma from four volunteers taken 24 and 25 hr after inhalation. Inhaled SCG solution, although producing peak plasma levels more than sevenfold greater than liposomal drug, was not detectable in 24-hr samples from any volunteer. The decline in plasma levels following inhalation of liposomal SCG (reflecting the absorption phase) was best described by a biexponential equation. The two absorption rate constants differed by more than an order of magnitude. The rapid absorption phase was probably due to free or surface-adsorbed SCG in the liposomal formulation, since the absorption rate constant for this phase did not differ significantly from the absorption rate constant for SCG in solution. The phase of slow drug absorption may then be attributed to absorption of drug released from vesicles. The data indicate that encapsulation of SCG prior to pulmonary administration prolonged drug retention within the lungs and altered its pharmacokinetics.
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ABSTRACT: Ultradeformable liposomes are stress-responsive phospholipid vesicles that have been investigated extensively in transdermal delivery. In this study, the suitability of ultradeformable liposomes for pulmonary delivery was investigated. Aerosols of ultradeformable liposomes were generated using air-jet, ultrasonic or vibrating-mesh nebulizers and their stability during aerosol generation was evaluated using salbutamol sulphate as a model hydrophilic drug. Although delivery of ultradeformable liposome aerosols in high fine particle fraction was achievable, the vesicles were very unstable to nebulization so that up to 98% drug losses were demonstrated. Conventional liposomes were relatively less unstable to nebulization. Moreover, ultradeformable liposomes tended to aggregate during nebulization whilst conventional vesicles demonstrated a "size fractionation" behaviour, with smaller liposomes delivered to the lower stage of the impinger and larger vesicles to the upper stage. A release study conducted for 2 h showed that ultradeformable liposomes retained only 30% of the originally entrapped drug, which was increased to 53% by inclusion of cholesterol within the formulations. By contrast, conventional liposomes retained 60-70% of the originally entrapped drug. The differences between ultradeformable liposomes and liposomes were attributed to the presence of ethanol or Tween 80 within the elastic vesicle formulations. Overall, this study demonstrated, contrary to our expectation, that materials included with the aim of making the liposomes more elastic and ultradeformable to enhance delivery from nebulizers were in fact responsible for vesicle instability during nebulization and high leakage rates of the drug.International Journal of Pharmaceutics 07/2012; 436(1-2):519-26. DOI:10.1016/j.ijpharm.2012.06.064 · 3.79 Impact Factor
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ABSTRACT: Multilamellar and oligolamellar liposomes were produced from ethanol-based soya phosphatidyl-choline proliposome formulations by addition of isotonic sodium chloride or sucrose solutions. The resultant liposomes entrapped up to 62% of available salbutamol sulfate compared with only 1.23% entrapped by conventionally prepared liposomes. Formulations were aerosolized using an air-jet nebulizer (Pari LC Plus) or a vibrating-mesh nebulizer (Aeroneb Pro small mesh, Aeroneb Pro large mesh, or Omron NE U22). All vibrating-mesh nebulizers produced aerosol droplets having larger volume median diameter (VMD) and narrower size distribution than the air-jet nebulizer. The choice of liposome dispersion medium had little effect on the performance of the Pari nebulizer. However, for the Aeroneb Pro small mesh and Omron NE U22, the use of sucrose solution tended to increase droplet VMD, and reduce aerosol mass and phospholipid outputs from the nebulizers. For the Aeroneb Pro large mesh, sucrose solution increased the VMD of nebulized droplets, increased phospholipid output and produced no effect on aerosol mass output. The Omron NE U22 nebulizer produced the highest mass output (approx. 100%) regardless of formulation, and the delivery rates were much higher for the NaCl-dispersed liposomes compared with sucrose-dispersed formulation. Nebulization produced considerable loss of entrapped drug from liposomes and this was accompanied by vesicle size reduction. Drug loss tended to be less for the vibrating-mesh nebulizers than the jet nebulizer. The large aperture size mesh (8 mum) Aeroneb Pro nebulizer increased the proportion of entrapped drug delivered to the lower stage of a twin impinger. This study has demonstrated that liposomes generated from proliposome formulations can be aerosolized in small droplets using air-jet or vibrating-mesh nebulizers. In contrast to the jet nebulizer, the performance of the vibrating-mesh nebulizers was greatly dependent on formulation. The high phospholipid output produced by the nebulizers employed suggests that both air-jet and vibrating-mesh nebulization may provide the potential of delivering liposome-entrapped or solubilized hydrophobic drugs to the airways.Journal of Pharmacy and Pharmacology 08/2006; 58(7):887-94. DOI:10.1211/jpp.58.7.0002 · 2.16 Impact Factor
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ABSTRACT: Inhalation of aerosolised drugs has become a well established modality in the treatment of localised disease states within the lung. However, most medications in aerosol form require inhalation daily at least 3–4 times because of the relatively short duration of resultant clinical effects. Some studies have been conducted with a view to sustaining release of drugs in the lung so as to prolong drug action, reduce side effects and improve patient compliance. Liposomes have been shown to have the potential to produce controlled delivery to the lung, since they can be prepared with phospholipids endogenous to the lung as surfactants. Up to now, many drugs have been incorporated into liposomes and tested in both human subjects and animal models as pulmonary delivery systems. Other biodegradable microspheres (MS) such as albumin MS and poly(lactide and/or glycolide) copolymer MS are also being investigated. In contrast to liposomes, these MS may be more physico-chemically stable both in vitro and in vivo. Thus, drugs entrapped in biodegradable MS may have a slower release rate and a longer duration of action than those incorporated in liposomes. The prodrug approach has been successful in producing long-lasting bronchodilators whilst conjugation of drugs to macromolecules provides a possible mechanism for controlled release of drugs for either localised or systemic actions. Sustained release in the lung can also be achieved by reducing the aqueous solubility of the drug or co-precipitating relatively insoluble materials with aqueous soluble drugs. In contrast, inclusion of drugs in cyclodextrins is unable to sustain drug release in the lung, which may be due to the premature breakdown of drug-cyclodextrin conjugates in vivo. Many interdependent factors, involving the lung, carrier, drug and device have been shown to influence the overall disposition of drugs in the respiratory tract after inhalation. Current studies on pulmonary delivery systems have many limitations, mainly due to the lack of suitable animal models and the chronic side effects of drug carriers have yet to be established. Thus, more inter-disciplinary collaboration is essential for the development of effective controlled drug delivery systems intended for administration to the lung.International Journal of Pharmaceutics 10/1995; 124(2):149–164. DOI:10.1016/0378-5173(95)00104-Q · 3.79 Impact Factor