The effect of a holding chamber on albuterol metered-dose inhaler product differences.

BACKGROUND: Three albuterol sulfate metered-dose inhaled (MDI) products (Ventolin HFA, Proventil HFA, and ProAir HFA) are marketed in the United States to provide the same total dose of albuterol sulfate. However, it is widely known that the fine particle dose (<5 µm) is the portion of the particle distribution that actually reaches the lungs and provides therapeutic benefit. OBJECTIVE: To examine the differences in particle size between products and how a valved holding chamber (VHC) can mitigate possible adverse effects. METHODS: Particle size distributions in each product were measured, with and without a VHC, and were analyzed by high-performance liquid chromatography. RESULTS: The only significant mean (SD) difference in total dose was between Proventil (75 [21] µg) and ProAir (107 [12] µg) (P < .01). The fine particle doses of all 3 products were significantly different: 21 (5) µg of albuterol sulfate for Ventolin, 40 (4) µg of albuterol sulfate for Proventil, and 64 (7) µg of albuterol sulfate for ProAir (P < .001 for all 3 cases). The VHC successfully removed the larger particle dose delivered by all 3 products (P ≤ .01) without reducing the fine particle dose (P > .05). CONCLUSION: Ventolin, Proventil, and ProAir should not be considered interchangeable products. In this study, the dose of albuterol sulfate likely to reach the lungs with Proventil or ProAir is 2 to 3 times that of Ventolin. As such, patients with asthma may require 3 additional puffs of Ventolin to achieve a clinical benefit similar to Proventil or ProAir. Because all 3 products contain 200 actuations, it also follows that Proventil or ProAir products may last a user 2 to 3 times longer than Ventolin.

Radiosensitization of Hs-766T Pancreatic Tumor Xenografts in Mice Dosed with Dodecafluoropentane Nano-Emulsion-Preliminary Findings.

Tumor hypoxia is an important mediator of radiation therapy resistance. We conducted a study to investigate whether an oxygen therapeutic based upon dodecafluoropentane (DDFP) nano-emulsion (NVX-108) could increase tumor PO2 in hypoxic tumors and improve radiation response. Pancreatic (Hs-766T) tumor xenografts were grown in the flanks of 29 SCID mice. Direct tumor PO2 measurements were performed in 9 mice treated with 0.3, 0.45 and 0.6 cc/kg NVX-108 (2% w/vol DDFP) in order to assess the dose dependent increase in tumor PO2. Twenty mice were randomized into 3 groups including control (no treatment), carbogen breathing treated with 12 Gy radiation, and carbogen breathing treated with 12 Gy radiation and NVX-108 (0.6 cc/kg NVX-108 administered as 30 minute IV infusion at time of radiation). Tumor volume was monitored to assess treatment efficacy. Results showed that tumor PO2 increased in NVX-108 treated mice up to 400% with the greatest effect seen at the highest dose of 0.6 cc/kg. Tumor growth was significantly reduced in both treatment groups relative to controls (p < 0.0001). The combination of carbogen, radiation, and NVX-108 demonstrated a 2-fold reduction in average tumor volume compared to carbogen plus radiation treatment (p = 0.01). Further study of NVX-108 as a radiation sensitizer is warranted.

Dodecafluoropentane emulsion decreases infarct volume in a rabbit ischemic stroke model.

PURPOSE: To assess the efficacy of dodecafluoropentane emulsion (DDFPe), a nanodroplet emulsion with significant oxygen transport potential, in decreasing infarct volume in an insoluble-emboli rabbit stroke model. MATERIALS AND METHODS: New Zealand White rabbits (N = 64; weight, 5.1 ± 0.50 kg) underwent angiography and received embolic spheres in occluded internal carotid artery branches. Rabbits were randomly assigned to groups in 4-hour and 7-hour studies. Four-hour groups included control (n = 7, embolized without treatment) and DDFPe treatment 30 minutes before stroke (n = 7), at stroke onset (n = 8), and 30 minutes (n = 5), 1 hour (n = 7), 2 hours (n = 5), or 3 hours after stroke (n = 6). Seven-hour groups included control (n = 6) and DDFPe at 1 hour (n = 8) and 6 hours after stroke (n = 5). DDFPe dose was a 2% weight/volume intravenous injection (0.6 mL/kg) repeated every 90 minutes as time allowed. After euthanasia, infarct volume was determined by vital stains on brain sections. RESULTS: At 4 hours, median infarct volume decreased for all DDFPe treatment times (pretreatment, 0.30% [P = .004]; onset, 0.20% [P = .004]; 30 min, 0.35% [P = .009]; 1 h, 0.30% [P = .01]; 2 h, 0.40% [P = .009]; and 3 h, 0.25% [P = .003]) compared with controls (3.20%). At 7 hours, median infarct volume decreased with treatment at 1 hour (0.25%; P = .007) but not at 6 hours (1.4%; P = .49) compared with controls (2.2%). CONCLUSIONS: Intravenous DDFPe in an animal model decreases infarct volumes and protects brain tissue from ischemia, justifying further investigation.

In vitro comparison of dodecafluoropentane (DDFP), perfluorodecalin (PFD), and perfluoroctylbromide (PFOB) in the facilitation of oxygen exchange.

The purpose is to prepare 2% w/v emulsions of dodecafluoropentane, perfluorodecalin, and perfluoroctylbromide and compare them for their ability to absorb oxygen. The oxygen uptake capability and volume expansion of each emulsion and the blank vehicle were evaluated in water at 21 degrees C and 37 degrees C. The average particle size of the dodecafluoropentane emulsion is < 400 nm stored at room temperature for 6 months. In comparison to water treated with either the blank vehicle, the perfluorodecalin emulsion, or the perfluoroctylbromide emulsion, the dodecafluoropentane emulsion absorbs 3 times more oxygen at 21 degrees C and 7 times more oxygen at 37 degrees C. Furthermore, a significantly higher in vitro expansion (5 times) is observed with the dodecafluoropentane emulsion at 37 degrees C. As such, DDFP has been hypothesized to be a better oxygen carrier and delivery agent in vivo. This may be applicable to a variety of hypoxic medical conditions where oxygen delivery might be therapeutically beneficial.

Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid.

The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPbetaCD results in a solid dosage form of PG301029 that is both soluble and stable in water.

Reformulation of a new vancomycin analog: an example of the importance of buffer species and strength.

The purpose of this research was to use our previously validated dynamic injection apparatus as a rapid method for screening pH-adjusted formulations of a new vancomycin analog, Van-An, for their potential to precipitate upon dilution. In 1 vial, Van-An was reconstituted according to the manufacturer's instructions. In a separate vial, the Van-An formulation's existing phosphate buffer species was supplemented with acetate buffer, which has a pKa in the desired range: between the pH values of the formulation (pH 3.9) and blood (pH 7.4). The formulations were injected using the dynamic injection apparatus into a flowing stream of isotonic Sorensen's phosphate buffer at rates of 0.25, 0.5, 1, and 2 mL/min. The peaks obtained with the spectrophotometer were reproducible for each injection rate/formulation combination. For the phosphate-buffered formulation, the least amount of precipitation was obtained at the 0.25 mL/min injection rate. Acetate buffer was able to substantially reduce such precipitation, even at the highest injection rate. The opacity peaks for the formulation with the acetate addition were significantly smaller (P < .05) than those obtained for the unaltered formulation at all 4 injection rates. The results suggest that acetate is a better buffer species than phosphate for the pH range defined. Furthermore, we present evidence to support a generally applicable approach to screening new formulations of drug products that may be clinically useful for reducing the incidence of phlebitis in humans.

Reformulation of a new vancomycin analog: An example of the importance of buffer species and strength.

The purpose of this research was to use our previously validated dynamic injection apparatus as a rapid method for screening pH-adjusted formulations of a new vancomycin analog, Van-An, for their potential to precipitate upon dilution. In 1 vial, Van-An was reconstituted according to the manufacturer's instructions. In a separate vial, the Van-An formulation's existing phosphate buffer species was supplemented with acetate buffer, which has a pKa in the desired range: between the pH values of the formulation (pH 3.9) and blood (pH 7.4). The formulations were injected using the dynamic injection apparatus into a flowing stream of isotonic Sorensen's phosphate buffer at rates of 0.25, 0.5, 1, and 2 mL/min. The peaks obtained with the spectrophotometer were reproducible for each injection rate/formulation combination. For the phosphate-buffered formulation, the least amount of precipitation was obtained at the 0.25 mL/min injection rate. Acetate buffer was able to substantially reduce such precipitation, even at the highest injection rate. The opacity peaks for the formulation with the acetate addition were significantly smaller (P<.05) than those obtained for the unaltered formulation at all 4 injection rates. The results suggest that acetate is a better buffer species than phosphate for the pH range defined. Furthermore, we present evidence to support a generally applicable approach to screening new formulations of drug products that may be clinically useful for reducing the incidence of phlebitis in humans.

Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid.

The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-ß-cyclodextrin (HPßCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPßCD results in a solid dosage form of PG301029 that is both soluble and stable in water.

Oral formulation of a novel antiviral agent, PG301029, in a mixture of gelucire 44/14 and DMA (2:1, wt/wt).

To develop an oral formulation for PG301029, a novel potent agent for the treatment of Hepatitis C virus infection, that not only has very low aqueous solubility but also degrades rapidly in water. The solubility of PG301029 was determined in water, various aqueous media, and several neat organic solvents. The stability of PG301029 was monitored at room temperature in buffers for 4 days, and in several neat organic solvents for up to 8 mo. Drug concentrations were measured by high-performance liquid chromatography (HPLC). Based on solubility and stability data, Gelucire 44/14 and DMA (N,N-dimethylacetamide) at a weight ratio of 2 to 1 were chosen as the formulation vehicle. After the vehicle was prepared, it was maintained in liquid form at approximately 40 degrees C until the PG301029 was dissolved. The final formulation product was a semisolid at room temperature. The bioavailability of the formulation was tested on 4 female BALB/c mice. PG301029 is insoluble in all tested aqueous media, while its solubility is promising in DMA. This compound is unstable in aqueous media and some organic solvents; however, it is stable in DMA. This proposed formulation is able to hold up to 10 mg/mL of drug and is stable at 4 degrees C. The shelf life for this formulation stored at 4degreesC is extrapolated to be greater than 4 years. This formulation dramatically increases the bioavailability of PG301029. This nonaqueous formulation solves the stability, solubility, and bioavailability problems for PG301029. This semisolid formulation can easily be incorporated into soft elastic capsules.

Prediction of precipitation-induced phlebitis: a statistical validation of an in vitro model.

To avoid phlebitis, new intravenous (IV) parenterals are often screened by injection into animals. This method is not only expensive and time consuming, it is also detrimental to the animals. An alternate method, focusing on precipitation as the cause, uses an in vitro dynamic injection model that requires less money and time and reduces the need for live models. Validation of the dynamic injection apparatus, for predicting mechanical phlebitis, is established. Twenty-one currently marketed IV products were injected into isotonic Sorenson's phosphate buffer flowing at 5 mL/min. The resulting opacities, produced by precipitation, are measured in an ultraviolet flow cell. These opacity data, coupled with literature reports on phlebitis occurrence, were used to generate a logistic regression that indicates the probability of phlebitis given an opacity value measured by the apparatus. Regression results are supported by a receiver operator characteristic curve that establishes the most ideal cut-off opacity value. This opacity value provides the highest combined sensitivity (statistical power) and specificity while minimizing false-positive and false-negative results. Both analyses show that an opacity value of 0.003 best delineates phlebitic and nonphlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93), and negative predictive value (0.78) indicate the model's predictive accuracy and reliability. These results support the use of the dynamic model in place of animals for preliminary phlebitis testing of new IV injectables.

Estimation of aqueous solubility of organic compounds by using the general solubility equation.

The general solubility equation (GSE) proposed by Jain and Yalkowsky was used to estimate aqueous solubility of 1026 non-electrolytes. The only parameters used in the GSE are melting points (MP) and octanol-water partition coefficients (Kow). No fitted parameters and no training set are employed in the GSE. The experimental solubility values were taken from the AQUASOL dATAbASE. The average absolute error and the root-mean-square error in the solubility estimates are 0.38 and 0.53 log units, respectively. Thus, with an observed MP and calculated Kow; the users can obtain a reasonable estimation of the aqueous solubility of any organic non-electrolyte.