Slow release formulations of inhaled rifampin.

Rifampin microspheres were prepared by spray drying using either polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) polymers in different drug to polymer ratios (90:10 to 5:95, w/w). The in-vitro release characteristics, particle-size distribution, and cytotoxicity (in an alveolar macrophage cell line) and pharmacokinetics in rats after pulmonary instillation were evaluated. Increasing the polymer content from 10% to 95% slowed down the in vitro drug release with PLGA particles showing a steeper change with increasing polymer content (100% to 20% drug release over 6 h) than PLA particles (88% to 42% drug release over 6 h). PLA microsphere formulations revealed lack of cytotoxicity and a mass median aerodynamic diameter (MMDA) of 2.22-2.86 mum, while PLGA particles were larger (MMDA of 4.67-5.11 mum). Pharmacokinetics differed among the formulations with the 10% PLA formulation showing a distinct sustained release (t (max) of 2 h vs 0.5 h of free drug) and a systemic bioavailability similar to that of free drug. Formulations with high polymer content showed a lower relative bioavailability (30%). This suggested that an optimal release rate existed for which a distinct amount of drug was delivered over an extended period of time.

Toxicokinetic study of recombinant human heparin-binding epidermal growth factor-like growth factor (rhHB-EGF) in female Sprague Dawley rats.

PURPOSE: To determine the toxicity and pharmacokinetics of recombinant heparin-binding epidermal growth factor-like growth factor in female Sprague Dawley rats following intra-bladder and intravenous administration. MATERIALS AND METHODS: rhHB-EGF was administered once daily for 6 or 27 days at doses of 3, 10, or 30 microg/kg. 125I-rhHB-EGF was administered on day 7 or 28 for pharmacokinetic analysis. Toxicity was assessed by general appearance and behavior, gross necropsy, blood chemistry and microscopic evaluation. RESULTS: Plasma AUCss of [125I] rhHB-EGF equivalents following IB administration for 7 days were 4.28+/-2.29, 7.75+/-2.70, and 7.11+/-1.42 ng ml(-1) h(-1) at doses of 3, 10, and 30 microg/kg, respectively. Following IV administration, the AUCss on day 7 increased from 27.0+/-2.66 to 124+/-5.09 and 385.11+/-7.57 ng ml(-1) h(-1) with increasing the dose from 3 to 10 and 30 microg/kg. Similar AUCss data was obtained after 28 day administration. No toxicity was evident upon gross examination. Histologic examination revealed subacute inflammation and lymphocytic infiltration of the urinary bladder in animals from all groups dosed by the IB route. CONCLUSIONS: Plasma and bladder concentrations of recombinant human [125I] rhHB-EGF equivalents were significantly lower following the IB route than following IV administration. Histologic tissue examination indicated no toxicity attributable to rhHB-EGF.

Laser-ablated nanofunctional polymers for the formulation of slow-release powders for dry powder inhalers: physicochemical characterization and slow-release characteristics.

Recently, dry powder inhalation (DPI) powders coated with nanometre-thin layers of biodegradable polymers, prepared using pulse laser deposition (PLD), have been evaluated as a slow-release formulation for DPI use, with the goal of improving pulmonary selectivity. This paper describes evaluation of the chemical stability of one potential polymer, poly lactic acid (PLA), during the ablation process, the resulting respirable properties and potential cytotoxicity of coated glucocorticoid powders, and the resulting sustained-release characteristics of PLA-coated glucocorticoids creating using PLD. Triamcinolone acetonide (TA) and budesonide (BUD) were used as two model glucocorticoids to determine pulmonary targeting (PT) in-vivo. The chemical stability of PLA was determined at various laser energy densities. The respirable fraction and the cytotoxicity of the micronized particles of TA and BUD, coated using optimum laser energy density, were determined. In-vitro dissolution profiles were generated for the coated/uncoated formulations and an ex-vivo receptor binding assay was used to determine PT in rats. Increasing laser energy density led to decreases in molecular weight and film density, and increases in degradation products, roughness and thickness of the film. The mean dissolution time of coated formulations of BUD was longer (4 h) than with the less lipophilic TA (2 h). This correlated well with a more pronounced pulmonary selectivity observed for coated BUD ex-vivo. Stability and the physical properties of the film correlated with the laser energy density. We observed a direct relationship between the dissolution rate of the uncoated and coated formulation and the degree of PT; however, physiochemical properties of the drug (e.g. lipophilicity) may also contribute to the improved PT.

Pulmonary targeting of sustained release formulation of budesonide in neonatal rats.

Systemic corticosteroids are widely used for the treatment/prevention of chronic lung disease (CLD) in premature infants. The use of the inhalation route for delivering corticosteroids has been widely recognized, however so far pre-term babies continue to be treated with oral glucocorticoids, such as dexamethasone. We hypothesize that the pulmonary administration of sustained release formulations of inhaled corticosteroids to pre-term infants will result in a higher benefit/risk ratio as compared to traditional inhalation therapy. To achieve a slow release formulation budesonide particles were coated with a very thin film of polylactic acid using a pulse laser ablation technique. Coated material was characterized with respect to the dissolution behavior and particle size. Ex vivo receptor binding studies were performed to monitor the cumulative lung, liver and brain receptor occupancies after adminstration in neonatal (10-11 days old) rats after intratracheal instillation of either uncoated budesonide or poly (l-lactic acid) (PLA) coated budesonide. The mean dissolution timed for the uncoated and the polymer coated formulations were 1.2 +/- 0.5 and 4.7 +/- 0.1 h, respectively (p < 0.05). No significant differences in the respirable fraction were found between coated and uncoated formulation (p>0.05). The average receptor occupancies in the lung, liver and brain after administration of uncoated budesonide were 58.4 +/- 12.9, 56.4 +/- 6.8 and 38.3 +/- 6.7%, respectively. However, after administration of PLA coated budesonide, the average AUC estimates in the lung, liver and brain were 75.8 +/- 3.7%, 46.6 +/- 14.5 and 29 +/- 7, respectively. The results from our study suggest sustained receptor occupancy in the lungs of neonatal rats after administration of PLA coated budesonide results in lower systemic exposure (as indicated by low liver receptor occupancy). The data strongly underscore the urgent need to develop sustained release pulmonary-targeted delivery systems of corticosteroids for the treatment of CLD in pre-term infants. The administration of inhaled corticosteroids using targeted drug-delivery systems will potentially result in higher local effects and a reduction in systemic exposure.

In vitro performance characteristics of valved holding chamber and spacer devices with a fluticasone metered-dose inhaler.

STUDY OBJECTIVE: To compare the in vitro aerosol deposition characteristics of several commercially available valved holding chamber (VHC) and spacer devices used with a fluticasone metered-dose inhaler (MDI). DESIGN: In vitro aerosol deposition study SETTING: University-affiliated research center. DEVICES: Seven VHC devices: BreatheRite, E-Z Spacer, EasiVent, AeroChamber, InspirEase, OptiChamber, and Space Chamber. Six spacer devices: OptiHaler, Aerosol Cloud Enhancer (ACE), Gentle-Haler, MediSpacer, Ellipse, and a 6-inch tube (1-inch inside diameter). INTERVENTION: The respirable dose (aerosol particles 1-5 microm) of fluticasone was determined by sampling 10 220-microg actuations from five runs with each spacer or VHC plus MDI combination, by using a well-established in vitro cascade impactor method. MEASUREMENTS AND MAIN RESULTS: Fluticasone aerosol was washed from the impactor with methanol and quantified by means of high-performance liquid chromatography. Differences among outcomes were determined with analysis-of-variance testing. Among spacers, Ellipse had the highest respirable dose (104 microg, p < 0.01). Respirable doses for the 6-inch tube (74.3 microg), Gentle-Haler (81.7 microg), and MediSpacer (82.6 microg) were no different from that of the MDI (p > 0.05), whereas respirable doses of OptiHaler (44.6 microg) and ACE (47.2 microg) were less than those of all other spacers (p < 0.001). Among VHC devices, respirable doses from EasiVent (35.6 microg), AeroChamber (47.0 microg), InspirEase (52.7 microg), OptiChamber (53.1 microg), and Space Chamber (58.3 microg) were not different (p > 0.05), whereas BreatheRite (13.1 microg) and E-Z Spacer (27.3 microg) respirable doses were less than those of the other VHC devices (p < 0.05). CONCLUSION: Spacers and VHC devices available in the United States do not demonstrate equivalent in vitro performance with the fluticasone MDI. The difference between highest and lowest respirable doses in each device category would likely lead to clinically relevant differences in the quantity of fluticasone delivered to a patient.

In vitro performance of two common valved holding chambers with a chlorofluorocarbon-free beclomethasone metered-dose inhaler.

STUDY OBJECTIVE: To compare in vitro aerosol deposition from a beclomethasone dipropionate metered-dose inhaler (MDI) containing hydrofluoroalkane propellant with that of the MDI in combination with two common valved holding chambers (VHCs) to evaluate how these VHCs affect the respirable dose of beclomethasone dipropionate. DESIGN: In vitro aerosol deposition study. SETTING: University research center. DEVICES: Beclomethasone dipropionate hydrofluoroalkane MDI alone, the MDI with OptiChamber VHC, and the MDI with AeroChamber-Plus VHC. INTERVENTION: The respirable dose (1-5-microm aerosol particles) of beclomethasone dipropionate was determined by sampling 10 80-microg actuations from five runs with each configuration (MDI alone, MDI with OptiChamber, and MDI with AeroChamber-Plus), using a well-established in vitro cascade impactor method. MEASUREMENTS AND MAIN RESULTS: Beclomethasone dipropionate aerosol was washed from the impactor with 50% methanol and quantified by means of high-performance liquid chromatography. Differences among outcomes were determined by using analysis of variance. Mean beclomethasone dipropionate respirable dose from AeroChamber-Plus (27.2 +/- 10.0 microg/actuation) was not significantly different (p>0.05) from that of the MDI alone (29.0 +/- 7.0 microg/actuation). OptiChamber respirable dose (12.8 +/- 6.0 microg/actuation) was less than half that produced by either the AeroChamber-Plus or the MDI alone (p=0.013). CONCLUSIONS: The OptiChamber and AeroChamber-Plus VHCs do not demonstrate equivalent in vitro performance when used with a beclomethasone dipropionate MDI that contains hydrofluoroalkane propellant. The respirable dose of beclomethasone dipropionate aerosol from the hydrofluoroalkane MDI was decreased by only 6% when the MDI was mated to an AeroChamber-Plus VHC and by 56% when used with an OptiChamber VHC.

Performance of a corticosteroid inhaler with a spacer fashioned from a plastic cold-drink bottle: effects of changing bottle volume.

Some clinicians advocate using metered-dose inhaler (MDI) spacers prepared from common household bottles. We evaluated the in vitro aerosol characteristics of fluticasone from the MDI alone and through spacers fashioned from 237-, 500-, 1000-, and 1500-mL polyethylene terephlate plastic cold drink bottles using a cascade impactor. Ten 110-microg actuations of fluticasone were sampled into the impactor during each of five runs with each configuration. The primary outcomes were the respirable dose (i.e., quantity aerosol 1.1-4.7 microm in size) and the quantity trapped in the oropharynx. The mean fluticasone respirable dose from the MDI alone (46.2 microg/actuation) was no different (p > 0.05) compared with the same MDI mated to any of the bottle spacers, regardless of volume. The mean quantity of fluticasone trapped in the oropharynx from the MDI alone (39.2 microg/actuation) was greater (p < 0.001) than the same MDI mated with any bottle spacer (range 1.5-3.5 microg/actuation). These data suggest that any of the bottle spacers tested would be an acceptable method to decrease the quantity of fluticasone that would deposit onto the oropharynx and thereby diminish the risk of topical adverse effects. Among the range of volumes tested, there was no relationship between spacer volume and respirable dose of fluticasone.

In vitro deposition of fluticasone aerosol from a metered-dose inhaler with and without two common valved holding chambers.

BACKGROUND: Previous in vitro aerosol deposition experiments indicate that the corticosteroid respirable dose from a metered-dose inhaler (MDI) can vary by threefold depending on the specific valved holding chamber (VHC) MDI combination. OBJECTIVE: We compared in vitro aerosol deposition from a fluticasone propionate MDI (Flovent, GlaxoSmithKline, Research Triangle Park, NC) to that of the same MDI used in combination with two VHCs (EasiVent, Dey, Napa, Ca; and AeroChamber-Plus, Monaghan Medical Corp, Plattsburgh, NY) to evaluate how these VHCs affect the respirable dose of fluticasone. METHODS: The respirable dose (aerosol particles 1 to 5 microm in size) of fluticasone was determined by sampling 5 x 110-microg actuations from each configuration (MDI alone, MDI plus AeroChamber-Plus, and MDI plus EasiVent) in multiples of ten using a well established, in vitro cascade impactor method. Fluticasone aerosol was washed from individual impactor stages with 50% methanol and quantified via ultraviolet high-pressure liquid chromatography. Differences among outcomes were determined using analysis of variance. RESULTS: Mean respirable dose from AeroChamber-Plus (47.9 +/- 6.9 microg/actuation) was not different (P > 0.05) from that produced by the MDI alone (50.3 +/- 2.2 microg/actuation). EasiVent respirable dose (27.0 +/- 3.6 microg/actuation) was less than that produced by either the AeroChamber-Plus or the MDI alone (P < 0.001). CONCLUSIONS: VHCs do not display equivalent in vitro performance with a fluticasone MDI. If a patient needs a VHC, clinicians should use available in vitro performance information to aid in selecting the best device.