In vitro and in vivo dose delivery characteristics of large porous particles for inhalation

Dunbar, Craig; Scheuch, G.; Sommerer, Knut; DeLong, Mark; Verma, Alka; Batycky, Rick

doi:10.1016/s0378-5173(02)00349-6

Cited by 80 publications

(31 citation statements)

References 20 publications

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“…The AIR powder is formulated in capsules that are punctured before inhalation. Each individual particle contains both drug and excipient within a large, low-density matrix (10,11). HIIP formulated in this manner has low cohesive forces but retains small effective aerodynamic diameter and can thus be aerosolized and delivered to the deep lung using a simple breath-actuated inhaler (12).…”

Section: System Descriptionmentioning

confidence: 99%

Dose Response of Inhaled Dry-Powder Insulin and Dose Equivalence to Subcutaneous Insulin Lispro

et al. 2005

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OBJECTIVE -To determine the pharmacokinetic (PK) and glucodynamic (GD) dose response of human insulin inhalation powder (HIIP) delivered via AIR particle technology and dose equivalence to subcutaneous (SC) insulin lispro.RESEARCH DESIGN AND METHODS -Twenty healthy, nonsmoking, male or female subjects (aged 29.6 Ϯ 6.9 years, BMI 23.2 Ϯ 2.3 kg/m 2 , means Ϯ SD) with normal forced vital capacity and forced expiratory volume were enrolled in an open-label, randomized, sevenperiod, euglycemic glucose clamp, cross-over trial. Each subject received up to four single doses of HIIP (2.6, 3.6, 5.2, or 7.8 mg) and three doses of SC lispro (6, 12, or 18 units) from 5 to 18 days apart.RESULTS -HIIP demonstrated a similar rapid onset but an extended time exposure and a prolonged duration of effect (late t 50% 412 vs. 236 min, P Ͻ 0.001) compared with SC lispro. The HIIP versus SC lispro doses of 2.6 mg vs. 6 units, 5.2 mg vs. 12 units, and 7.8 mg vs. 18 units achieved similar PK area under the serum immunoreactive insulin (IRI) concentration-versustime curve from time zero until the serum IRI concentrations returned to the predose baseline value [AUC (0-tЈ) ] and GD (G tot ) responses. The median insulin (t max ) was not different between HIIP and SC lispro (45 min for both), although the median time of return to baseline for PK was apparently longer for HIIP compared with SC lispro (480 vs. 360 min). Relative bioavailability and relative biopotency of HIIP were consistent across doses (8 and 9%).CONCLUSIONS -While the time-action profile was longer for HIIP than for SC lispro, both treatments showed rapid initial absorption and similar overall PK exposure and GD effect. HIIP was as well tolerated as SC lispro, thereby offering a promising alternative to injectable insulin therapy. Diabetes Care 28:2400 -2405, 2005T he disease burden of diabetes continues to grow and currently affects Ͼ18 million Americans and their families (1). Despite increased use of diabetes medications (without, however, increased utilization of insulin), overall diabetes control A1C among individuals diagnosed with diabetes in the U.S. has not improved, with A1C rising from 7.7 to 7.9% during the final decade of the last century (2). These data emphasize a need for alternative diabetes therapies with earlier more physiologic use of insulin.The delivery of insulin by the lung may provide an attractive alternative for many patients with diabetes (3-8). However, alternative insulin delivery systems must meet certain pharmacokinetic (PK) and glucodynamic (GD) requirements to reach maximum utility (9). Specifically, the dose-response characteristics of inhaled insulin should be similar to those of injectable insulins, like human regular insulin or fast-acting insulin analogs such as insulin lispro. Moreover, inhaled insulin should demonstrate satisfactory dose reproducibility; that is, intrasubject variability of inhaled insulin should be similar to or better than that of injectable insulin. Finally, the ratio of dose equivalence between inhaled insulin an...

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Section: System Descriptionmentioning

confidence: 99%

Dose Response of Inhaled Dry-Powder Insulin and Dose Equivalence to Subcutaneous Insulin Lispro

et al. 2005

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“…A number of in vivo (Walsh et al, 1977;Foord et al, 1978;Chan & Lippmann, 1980;Stahlhofen et al, 1980Stahlhofen et al, , 1981Emmett & Aitken, 1982;Svartengren et al, 1994;Dunbar et al, 2002) and in vitro studies (Cheng et al, 1999(Cheng et al, , 2001Lin et al, 2001;Grgic et al, 2004b;DeHaan & Finlay, 2004;Grgic et al, 2004a;Heenan et al, 2004;Zhang et al, 2007;Zhou et al, 2011;Shinneeb & Pollard, 2012) have been conducted in order to develop an understanding of the flow and particle dynamics in the extrathoracic airways. In vivo experiments are costly and complex to perform, and accurate results are difficult to obtain due to spatial resolution and tissue attenuation limit (Grgic et al, 2004b).…”

Section: Introductionmentioning

confidence: 99%

Direct numerical simulations of flow in realistic mouth–throat geometries

Nicolaou

Zaki

2013

Journal of Aerosol Science

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“…In addition, distributions that include a wide range of both large and small particle sizes have shown a lack of control in depositing the drug at the specific sites of infection [13]. To deal with these problems, recent work has focused on "large porous" particles exhibiting geometric diameters larger than 10 μm but with aerodynamic diameters of ∼1-3 μm [14][15][16][17]. Large porous particles exhibit the aerodynamics of smaller particles while maintaining a size large enough to resist uptake by alveolar macrophages [18]; however, a narrow aerodynamic diameter is still desired.…”

Section: Introductionmentioning

confidence: 99%

NanoCipro encapsulation in monodisperse large porous PLGA microparticles

Arnold

Gorman

Schieber

et al. 2007

Journal of Controlled Release

117

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Pulmonary drug delivery of controlled release formulations may provide an effective adjunct approach to orally delivered antibiotics for clearing persistent lung infections. Dry powder formulations for this indication should possess characteristics including; effective deposition to infected lung compartments, persistence at the infection site, and steady release of antibiotic. Large porous particles (∼10-15 μm) have demonstrated effective lung deposition and enhanced lung residence as a result of their large diameter and reduced clearance by macrophages in comparison to small microparticles (∼1-5 μm). In this report, Precision Particle Fabrication technology was used to create monodisperse large porous particles of poly(D,L-lactic-co-glycolic acid) (PLGA) utilizing oils as extractable porogens. After extraction, the resulting large porous PLGA particles exhibited a low density and a web-like or hollow interior depending on porogen concentration and type, respectively. Ciprofloxacin nanoparticles (nanoCipro) created by homogenization in dichloromethane, possessed a polymorph with a decreased melting temperature. Encapsulating nanoCipro in large porous PLGA particles resulted in a steady release of ciprofloxacin that was extended for larger particle diameters and for the solid particle morphology in comparison to large porous particles. The encapsulation efficiency of nanoCipro was quite low and factors impacting the entrapment of nanoparticles during particle formation were elucidated. A dry powder formulation with the potential to control particle deposition and sustain release to the lung was developed and insight to improve nanoparticle encapsulation is discussed.

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In vitro and in vivo dose delivery characteristics of large porous particles for inhalation

Cited by 80 publications

References 20 publications

Dose Response of Inhaled Dry-Powder Insulin and Dose Equivalence to Subcutaneous Insulin Lispro

Dose Response of Inhaled Dry-Powder Insulin and Dose Equivalence to Subcutaneous Insulin Lispro

Direct numerical simulations of flow in realistic mouth–throat geometries

NanoCipro encapsulation in monodisperse large porous PLGA microparticles

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