A theoretical model is outlined for predicting the time evolution of total mass, mean molecular weight, and drug release for the case of a spherical bulk-eroding microsphere, prepared by a double emulsification procedure and containing a hydrophilic drug, such as a protein or peptide. Explicit analytical formulae are derived for calculating the time evolution of measurable macroscopic characteristics, such as drug release or mean molecular weight. Microsphere hydration, polymer erosion, and drug release phases are each described. Results indicate that polymer degradation by only random-chain scission or only end scission (or unzipping) cannot explain experimentally observed kinetics of particle mass loss and molecular weight change; thus, a combined model (incorporating both random and end scission) is proposed. A general methodology for determining the microscopic transport coefficients (such as polymer degradation rate constant or drug diffusion coefficient) from erosion and release data is outlined. This paradigm is applied to the specific case of 50:50 poly(D,L-lactic-co-glycolic acid (PLGA) microspheres encapsulating glycoprotein 120 (gp 120), a candidate AIDS vaccine. Predictions permit comparisons with experimental data for mean weight- and number-averaged molecular weights, as well as for mass loss and protein release. Other comparisons are made with data appearing in the literature for release of tetanus toxoid from PLA and PLGA microspheres of variable molecular weight. Agreement between theory and experiment is observed.

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Inhaled drugs offer advantages, such as rapid onset of action, but require formulations and delivery systems that reproducibly and conveniently administer the drug. CVT-301 is a powder formulation of levodopa delivered by a breath-actuated inhaler that has been developed for treating OFF episodes (motor fluctuations between doses of standard oral levodopa) in patients with Parkinson's disease (PD). We present preclinical, phase 1, and phase 2 results for CVT-301. In dogs insufflated with a levodopa powder, plasma levodopa peaked in all animals 2.5 min after administration; in contrast, in dogs dosed orally with levodopa plus carbidopa, plasma levodopa was not detected until 30 min after administration. In 18 healthy persons, comparisons between inhaled CVT-301 and oral carbidopa/levodopa showed analogous differences in pharmacokinetics. Among 24 PD patients inhaling CVT-301 as a single 50-mg dose during an OFF episode, 77% showed an increase in plasma levodopa (>400 ng/ml) within 10 min versus 27% for oral dosing with carbidopa/levodopa at a 25-mg/100-mg dose. Improvements in timed finger tapping and overall motor function (Part III of the Unified Parkinson's Disease Rating Scale) were seen 5 and 15 min after administration, the earliest assessment time points. For average and best change, the improvements were statistically significant compared to placebo. The most common adverse event was cough; all cough events were mild to moderate, occurred at the time of inhalation, resolved rapidly, and became less frequent after initial dosing. These results support further development of CVT-301 for better management of PD.

Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.

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...