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US 7648696 B2
A stable composition for rapid delivery by inhalation to the lungs, and subsequently to the bloodstream, is provided. The composition comprises a therapeutically effective amount of delta-9-tetrahydrocannabinol in a pharmaceutically-acceptable semiaqueous solvent comprising an alcohol, water and a glycol. A composition comprising volumetric ratios of ethanol:water:propylene glycol selected from those in the range of from 10-70:10-30:20-80, respectively, having a combined total of 100 is also provided. A sterile and/or preserved sealed unit-or multi-unit dosage form of delta-9-tetrahydrocannabinol is further provided.
1. A stable composition for rapid delivery by inhalation to the lungs, and subsequently to the bloodstream, the composition comprising a therapeutically effective amount of delta-9-tetrahydrocannabinol in a pharmaceutically-acceptable semiaqueous solvent consisting essentially of an alcohol, water and a glycol, in amounts sufficient
(i) to aerosolize the composition to a mean mass median aerodynamic diameter in the range of from about 1 up to about 10 μM;
(ii) to enhance partitioning by producing a stable clear solution near the solubility point of the delta-9-tetrahydrocannabinol;
(iii) wherein the concentration of glycol is about 20% to about 65% of the solvent; and
(iv) wherein the concentration of the alcohol is 20% to about 70% of the solvent.
2. The composition of
3. The composition of
4. The composition of
5. The composition of
6. The solvent of
7. The solvent of
8. The solvent of
9. The composition
10. The composition
This application is a continuation-in-part of U.S. patent application Ser. No. 09/639,289, filed Aug. 15, 2000, which is a non-provisional of U.S. Provisional Application No. 60/150,023, filed Aug. 20, 1999. This application claims priority to all such previous applications, and such applications are hereby incorporated herein by reference.
The present invention relates to a fast-acting delivery system for delta-9-tetrahydrocannabinol (dronabinol) to improve bioavailability. More particularly, it provides a stable composition for delivery by inhalation to the lungs, and subsequently to the bloodstream, the composition comprising a therapeutically effective amount of delta-9-tetrahydrocannabinol (also known as “delta-9-THC”) and a pharmaceutically-acceptable semiaqueous solvent.
Dronabinol, a synthetic version of delta-9-tetrahydrocannabinol (delta-9-THC), is currently approved by regulatory authorities for use as an antiemetic in cancer chemotherapy as well as an appetite stimulant for patients afflicted with the AIDS virus. The product is currently marketed under the commercial name Marinol® as an oral soft gelatin capsule in which the drug substance is dissolved in sesame oil.
Dronabinol is the principal psychoactive agent in marijuana and has a number of complex effects on the central nervous system, including central sympathomimetic activity. Dronabinol also has anti-nausea/antiemetic activity. The mechanism whereby dronabinol acts to reduce nausea and emesis is not well understood, in part because the neuro-pharmacology of the vomiting center and its connections to input centers is not known in sufficient detail. Dronabinol, however, appears to act via a mechanism distinct from that of other antiemetics which function, typically, by dopaminergic antagonism, such as, phenothiazines, butyrophenones, or benzamides or that of H, antagonists, which are used most commonly for prevention of motion sickness and are included in many antiemetic regimens to suppress the extrapyramidal effects of the neuroleptic anti-dopaminergics.
Bioavailability of the current formulation ranges from 10-20% due to a high first pass metabolism associated with oral administration. The current formulation has an onset of action ranging from 0.5 to 1 hour. In addition, maximum concentrations may not be reached until several hours after oral administration.
As discussed, dronabinol is almost completely absorbed (90-95%) after single oral doses. Dronabinol has an extensive first pass hepatic metabolism and, also, high lipid solubility. As a result, only 10% to 20% of an orally administered dose will be found in systemic circulation at peak levels, the balance being sequestered in lipid tissues or having been metabolized during the first pass. Dronabinol and its principle active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentration of both the parent drug and the metabolite peaks at approximately 2 to 4 hours after oral dosing and declines over several days. Values for clearance average are about 0.2 L/kg/hr, but are highly variable due to the complexity of cannabinoid distribution.
The elimination phase of dronabinol can be described using a two-compartment model with an initial alpha half-life of about 4 hours and a terminal beta half-life of 25 to 36 hours.
Because of its very high lipid solubility, dronabinol is sequestered in fatty tissues leading to a very large apparent volume of distribution, approximately 10 L/kg and to the creation of a depot compartment from which dronabinol is excreted at low levels for prolonged periods of time. This depot compartment produces the long beta half-life excretion phase for dronabinol. Biliary excretion is the major route of elimination with about half of the oral dose being recovered from the feces within 72 hours as contrasted with 10% to 15% recovered from urine.
The major urinary metabolite in humans following oral administration is 11-nor-9-lc carboxy-delta-9-tetrahydrocannabinol. It accounts for approximately 27% of the total THC metabolites excreted in urine. Less than 5% of an oral dose is recovered unchanged in the feces.
It would be desirable to improve bioavailabity and quicken onset of action for the above indications as well as for the treatment of alternative conditions, such as spinal cord spasticity, glaucoma, and Alzheimer's disease. Alternative routes previously suggested to overcome oral delivery limitations include the administration of drugs (including delta-9-tetrahydrocannabinol) through inhalation. It has been demonstrated in the literature, for example, that smoking marijuana cigarettes (the main constituent being dronanbinol, i.e., delta-9-THC) results in improved bioavailability (60-70%). However, there are obvious disadvantages relating to smoking marijuana, including raw material impurities, depression of alveolar macrophage activity, and bronchial irritation. Another approach suggested in initial reports at a meeting on Feb. 24, 1998, sponsored by the Institute of Medicine, National Academy of Sciences, Division of Neuroscience and Behavioral Health in Washington, D.C., was to study and use particle size data developed in a conventional nebulizer system to try to enhance bioavailability of delta-9-tetrahydrocannabinol after deep lung administration. Among the suggested routes of administration suggested by the prior art are those using aerosol formulations to be inhaled as described in Volicer, U.S. Pat. No. 5,804,592, granted Sep. 8, 1998, based on Provisional Application with a priority date of May 7, 1997. However, as presently advised, there has been no prior disclosure of experiments which used formulations comprising delta-9-tetrahydrocannabinol and semiaqueous solvents comprising judiciously selected volumetric ratios of alcohol, water and pharmaceutically acceptable glycols to enhance partitioning, and no evidence of enhanced bioavailability in warm-blooded animals, including humans, has been known for such compositions prior to the present invention. It still remains desirable, therefore, to develop a new safe, fast acting delivery system for delta-9-tetrahydrocannabinol to improve bioavailability, and such a system is the subject matter of the present invention.
In accordance with the present invention there are provided stable compositions for rapid delivery by inhalation to the lungs, and subsequently to the bloodstream, the compositions comprising a therapeutically effective amount of delta-9-tetrahydrocannabinol in a pharmaceutically-acceptable semiaqueous solvent comprising an alcohol, water and a glycol, in relative volumetric amounts sufficient:
(i) to aerosolize the composition to a mean mass median aerodynamic diameter in the range of from about 1 up to about 10 μM; and
(ii) to enhance partitioning by producing a stable clear solution near the solubility point of the delta-9-tetrahydrocannabinol.
Among the preferred features of the invention are such compositions wherein: the delta-9-tetrahydrocannabinol comprises from about 0.1 to about 200 mg/mL, and especially 25 and 50 mg/mL; the solvent comprises ethanol, water and propylene glycol; the volumetric ratios of ethanol:water:propylene glycol are selected from those in the range of from about: 10-70:10-30:20-80, respectively, having a combined total of 100; the volumetric ratios of ethanol:water:propylene glycol are selected from those in the range of from 10-70:10:20-80, respectively, having a combined total of 100; the volumetric ratios of ethanol:water:propylene glycol are 35:10:55, respectively, having a combined total of 100.
Also contemplated by the present invention are sterile or preserved sealed single-unit and/or multi-unit dosage forms of delta-9-tetrahydrocannabinol comprising a container and a stable composition for rapid delivery by inhalation to the lungs and subsequently to the bloodstream, as first defined above, and especially those wherein the container comprises Type I Amber Glass with a suitable liner.
Numerous experiments have shown that the drug formulation is critical for delta-9-tetrahydrocannabinol to be effectively delivered to the lung rapidly. It has been discovered that effective formulations must be stable, aerosolized to a particle size less than or equal to 10 μM to reach the lung, and the drug must readily partition out of the delivery system in order to transport across biological membranes and reach the blood stream. The physico-chemical characteristics of delta-9-tetrahydrocannabinol raw drug material lend themselves to various formulations, including solutions. Delta-9-tetrahydrocannabinol is virtually insoluble in water (0.003 g/mL). It is known that the drug substance is extremely lipophilic, with a reported oil/water coefficient of 9,400,000 (Garret and Hunt, Journal of Pharmaceutical Sciences, Vol. 63, No. 7, pages 1056-1064, 1974; and Thomas et al., The Journal of Pharmacology and Experimental Therapeutics, Vol. 255, No. 1, pages 624-630, 1990). These factors have been considered in developing the compositions of this invention.
Also critical to the present invention is the need for selecting substances, which will release the drug for absorption or partition it from the dosage form. The lipophilic nature of delta-9-tetrahydrocannabinol suggests that formulations made primarily of lipophilic excipients such as oils, for example, sesame seed oil, currently approved for oral unit dosage use, would not be desirable because the drug would not partition readily. In the case of oily excipients, delta-9-tetrahydrocannabinol would have a strong affinity for the formulation and would slowly partition out, resulting in slow absorption, exactly the problem sought to be avoided.
Semiaqueous solutions, that is, combinations of organic solvents with small, effective amounts of water, lend themselves to making formulations with delta-9-tetrahydrocannabinol with unexpected increases in partitioning, apparently because the drug has a poor affinity for the water within the formulation. Because of the increased ease of partitioning, once released deeply in the lung from the dosage forms of the present invention, delta-9-tetrahydrocannabinol is able to cross cell membranes rapidly, traverse the alveolar epithelial cells, interstitium, and endothelium to reach the blood stream (Thompson, “Pharmacology of Therapeutic Aerosols” Chapter 2, in Pharmaceutical Inhalation Aerosol Technology, Ed. Hickey, Marcel Dekker, Inc. New York, pages 29-37,1992). As a further advantage, the formulations of delta-9-tetrahydrocannabinol and semiaqueous solvents of the present invention may be aerosolized more easily than oil based systems.
As will be shown hereinafter, delta-9-tetrahydrocannabinol readily dissolves in ethanol and in equal parts of ethanol and propylene glycol to form clear solutions which, for purposes of the present invention, are “stable,” that is, remain clear through three cycles of freeze/thaw. Such compositions, however, do not meet the ease of partitioning required by the present invention because the delta-9-tetrahydrocannabinol prefers to stay in the organic phase and only slowly releases itself from the dosage form at the intended site of absorption. As described in detail below, water can be added to the organic phase, and the delta-9-tetrahydro-cannabinol is able to remain in solution, near the solubility point of the drug, and, unexpectedly, partitioning is enhanced and in vivo bioavailability is accelerated, especially in comparison with intravenous administration of the same formulation. The experiments have also shown that as the water content of the semiaqueous solvent increases and the ethanol content decreases beyond a certain level, the drug readily falls out of solution, and such unstable formulations no longer function as dosage forms within the scope of the invention.
The citation to Thomas, mentioned above, teaches that aerosol particle size has an influence on the deposition pattern of many drugs in the lung. In general, deposition is successful at a mean mass median aerodynamic diameter in the range of from about 1 μM to about 10 μM. For best results in lung delivery, it is known from Thomas that delta-9-tetrahydrocannabinol should be targeted for delivery deep in the lung, and this is facilitated by using aerosol particle diameters of less than about 3 μM, a size which is readily, but unexpectedly, obtained with the compositions of the present invention, using conventional nebulizers, as will be shown in the examples which follow, and in conventional metered dose inhalers.
In one embodiment of the invention, the delta-9-tetrahydrocannabinol comprises from about 0.1 to about 300 mg/mL. The delta-9-tetrahydrocannabinol can comprise any suitable amount, such as, e.g., about 0.1, about 0.5, about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, and about 300 mg/mL.
In one embodiment, the solvent comprises ethanol, water and propylene glycol. In one embodiment, the volumetric ratios of ethanol:water:propylene glycol are selected from those in the range of from about: 10-70:10-30:20-80, respectively, having a combined total of 100.
In one embodiment, the volumetric ratios of ethanol:water:propylene glycol are selected from those in the range of from 10-70:10:20-80, respectively, having a combined total of 100.
In one embodiment, the volumetric ratios of ethanol:water:propylene glycol are 35:10:55, respectively, having a combined total of 100.
The solvent can comprise any suitable solvent or combination of solvents. In one embodiment, the solvent comprises an alcohol, such as, for example, ethanol. The solvent can comprise any suitable amount of alcohol, such as, e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69% and about 70% alcohol (v/v).
In one embodiment, the solvent comprises a glycol. The glycol can be any suitable glycol, such as, e.g., propylene glycol. The solvent can comprise any suitable amount of glycol, such as, e.g., about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79% and about 80% glycol (v/v).
In one embodiment, the solvent comprises water. In one embodiment, the solvent comprises a suitable amount of water to bring to total percentage of ingredients in the solvent to 100%. In this embodiment, the amount of water in the solvent will be determined by the amount of other components in the solvent. For example, in one embodiment, the solvent comprises 35% ethanol and 55% propylene glycol. In this case, the amount of water to bring the total percentage to 100% would be 10%.
The solvent can comprise any suitable amount of water, such as, e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29% and about 30% water (v/v).
In one embodiment of the present invention 1-250 mg of delta-9-tetrahydrocannabinol (dronabinol) is dissolved per mL of final composition in USP in 5-95% v/v of ethanol, USP (190 proof), or an obvious equivalent, e.g., isopropanol, in a suitable mixer. Next, add 20-80% v/v propylene glycol, USP, or an obvious equivalent, such as polypropylene glycol, polyethylene glycol, and the like, and 10-25% v/v purified water and mix, and then filter and transfer to a storage tank. A suitable concentration of delta-9-tetrahydro-cannabinol in pharmaceutical compositions for inhalation is 0.05 to 15% (by weight).
In another embodiment of the present invention, the concentration of delta-9-THC is from 0.02 to 5%. Another illustrative embodiment of the present invention is a concentration from 0.1 to 4%. In yet another embodiment of the present invention the formulations of the invention can also include minor but effective amounts of anti-oxidants, surfactants, buffers, sodium chloride, pH adjusting agents, bacteriostats, stabilizers, preservatives, and the like.
In one embodiment of the present invention, the formulations are transferred by conventional means to unit-dose or multi-dose sealed containers, such as ampules and vials, preferably made of amber glass Types I, II and III, with a suitable liner.
The quantity of delta-9-tetrahydro-cannabinol can vary widely. For example, in one embodiment of the present invention the amount may be from about 0.001 to about 35 mg/kg of body weight administered one to six times per day. The dose administered to an animal, such as a human, should be sufficient to effect a therapeutic response over a reasonable time frame. The dose will be determined by the strength of the particular compositions employed and the condition of the subject, as well as the body weight of the subject to be treated. The size of the dose also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular composition. An illustrative dosage of delta-9-tetrahydrocannabinol for administration by inhalation is about 0.01 to 100 about mg/kg per day, given in 2-4 divided doses. Yet another illustrative example is dosage of about 0.01 to about 35 mg/kg per day. A third, illustrative example of the present invention is a dosage of about 0.05 to about 5 mg/kg per day. Any suitable amount of delta-9-THC can be administered, such as, e.g., about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg or more.
The following examples illustrate the present invention. They are not to be construed to limit the claims in any manner whatsoever. Semiaqueous solvent ratios are volumetric, i.e., v/v, and total 100 parts.
The physical stability of delta-9-tetrahydrocannabinol in varying ratios of ethanol, USP, purified water and propylene glycol was determined by placing 0.3 ml of delta-9-tetrahydrocannabinol (standard, 100 mg/mL) in a 16×100 mm Pyrex tube, adding 2.7 mL of absolute ethanol for a total volume of 3.0 mL, and shaking the tube until mixed. This resulted in a 100:0:0 ethanol (E); water (W): propylene glycol (PG) ratio and a drug concentration of 10 mg/mL. The foregoing steps were repeated for 12 more ratios according to Table 1 below, which lists volumes of standard delta-9-tetrahydrocannabinol (delta-9-THC), ethanol (Alcohol), purified water (Water), and propylene glycol, and the visual inspection results recorded after the samples are placed on a freeze/thaw (F/T) cycle for three turns.
As can be seen from Table 1, in varying ratios of ethanol/propylene glycol, delta-9-tetrahydrocannabinol is able to remain in solution in the presence of controlled amounts of water. However, as the water content increases and ethanol content decreases beyond a certain level, the drug readily falls out of solution.
The procedure of Examples 1-7 was repeated to assess solubility of increasing concentration of delta-9-tetrahydrocannabinol in a selected vehicle. Based on freeze/thaw data generated with delta-9-tetrahydrocannabinol using different solvent ratios (Table 1) a vehicle comprised of alcohol/water/propylene glycol in a volumetric ratio of 35:10:55 was selected. This ratio allows for good solubility of the drug while keeping the alcohol concentration low enough for ease of manufacturing. Results of the experiments are set forth in Table 2 below.
The results illustrate that if the alcohol concentration is reduced below approximately 35%, drug droplets begin to form indicating that the drug is below its solubility point in the vehicle. The results also indicate that delta-9-tetrahydrocannabinol concentrations in excess of 100 mg/mL are able to be manufactured with this formulation, but 200 mg/mL cannot. From ease of manufacturing and expected doses of delta-9-tetrahydrocannabinol required for inhalation, a drug concentration of 25 mg/mL in the formulation of Example 8 (35:10:55 Alcohol:Water:Propylene Glycol) was evaluated in preclinical studies. A Pari LC Plus Nebulizer was used in a conventional fashion and it generated aerosolized particles having a mean mass median aerodynamic diameter of 2.96 ηM.
Two animal species, rat and dog, were administered the formulation in a 14 day multiple dose inhalation study with a nebulizer. Results from the pharmacokinetic portion of the study indicated comparability between tmax values found for intravenous and inhaled delivery. Tmax values are summarized for both single (intravenous and inhalation) and for multiple dose (intraveneous and inhalation) of delta-9-tetrahydrocannabinol in Table 3, as follows:
The data in the foregoing examples show that a semiaqueous formulation of delta-9-tetrahydrocannabinol in accordance with the present invention can produce a stable clear solution near the solubility point of the drug. Moreover, because delta-9-tetrahydrocannabinol has poor affinity for the formulation, it is able to partition out and transport across cell membranes to reach the bloodstream rapidly. This has been demonstrated by the comparative tmax values achieved in single dose intravenous and 14 day multiple dose inhalation studies as detailed above.
This example demonstrates the pharmacokinetics and safety of dronabinol after pulmonary administration.
A. Overall Study Design and Plan
A parallel group, double-blind, randomized, placebo-controlled study of six ascending single and multiple inhalation dose administrations and one single oral dose of dronabinol in healthy male and female subjects. Exclusions included recent tobacco use, marijuana consumption, pulmonary dysfunction or evidence of any significant medical conditions. A total of 56 subjects were enrolled into 7 treatment groups. The treatment groups were as follows:
Treatment A: 5 mg dronabinol (Marinol® oral capsule)
Treatment B: 0.2 mg dronabinol (1 inhalation per dose)
Treatment C: 0.4 mg dronabinol (2 inhalations per dose)
Treatment D: 1.0 mg dronabinol (5 inhalations per dose)
Treatment E: 1.4 mg dronabinol (7 inhalations per dose)
Treatment F: 2.0 mg dronabinol (10 inhalations per dose)
Treatment G: 2.4 mg dronabinol (12 inhalations per dose)
Treatment A consisted of a single oral administration on Day 1. Treatments B through G consisted of a single inhalation on Day 1, followed by daytime inhalations four times daily (every 5 hours, with 9 hours between the last daytime and following first morning dose) on Days 3-5. In each treatment group of 8 subjects, two received placebo and six received dronabinol. 51 subjects completed the study. Seven of 8 subjects completed the Treatment D and Treatment F regimens, and 5 of 8 subjects completed the Treatment G regimen.
Subjects receiving Treatment A were in a fasted state following a 10-hour overnight fast. Subjects receiving Treatments B through G were in a fasted state following a 10-hour overnight fast on Day 1. On Days 3 through 5 the subjects were in a fed state having had breakfast, lunch, dinner, or a snack within 1 hour of dosing.
Blood samples were obtained on Days 1 and 5 at pre-dose, 2, 5, 10, 15, 20, 30, 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36 and 48 hours. After dosing on Day 5, a 72-hour sample was also obtained. Samples were also collected prior to dosing at 53, 58 and 63 hours; prior to dosing at 72, 77, 82 and 87 hours; prior to dosing at 96, 101, 106 and 111 hours and at 111:02, 111:05, 111:10, 111:15, 111:20, 111:30, 111:45 (hr:min) and 112, 112.5, 113, 114, 115, 116 and 117 hours; 120, 123 and 135 hours; 159 hours and 183 hours. Samples from subjects receiving placebo were assayed only at representative timepoints. All subjects receiving placebo had no quantifiable levels of dronabinol or 11-OH-delta-9-THC reported in any of their samples.
Plasma concentrations of delta-9-THC and the 11-OH metabolite (11-OH-delta-9-TCH) were analyzed by Liquid Chromotography/Mass Spectroscopy/Mass Spectroscopy (LC/MS/MS). The limit of quantitation was 0.50 ng/mL.
Pharmacokinetic parameters were determined for dronabinol (delta-9-THC) and its principal active metabolite 11-OH-delta-9-THC.
The analysis was a two-stage procedure. Steady-state was evaluated by regressing the 63-, 87-, and 111-hour dronabinol and 111-OH-delta-9-THC concentrations over time. The 58-, 82-, and 106-hour; 53-, 77-, and 101-hour, and the 48-, 72-, and 96-hour dronabinol and 11-OH-delta-9-THC concentrations were also evaluated by regression. Steady-state was achieved when the slope was not statistically different from zero.
Dose adjusted parameters were analyzed using analysis of variance (ANOVA) with treatment in the model to determine dose proportionality. Dose adjustment was made by dividing the parameter value by the dose (in mg). The 90% confidence intervals about the difference of all painwise comparisons were also created.
The mean (SD) pharmacokinetics parameters for dronabinol after single dose dronabinol administration are presented in Table 4.
The mean (SD) pharmacokinetics parameters for dronabinol after multiple dose dronabinol administration are presented in Table 5.
The data shows that all inhalation treatments resulted in similar shapes of plasma dronabinol concentration-time profiles with rapidly reached peak concentrations and equally quick decline in post peak concentrations on both Days 1 and 5. On Day 1, the mean Tmax ranged from 0.032 hours (Treatment D) to 0.041 hours (Treatment F), and the mean Cmax ranged from 5.259 ng/mL (Treatment B) to 73.237 ng/mL (Treatment F). On Day 5, the mean Tmax ranged from 0.034 hours (Treatments D-F) to 0.039 hours (Treatment C), and the mean Cmax ranged from 12.123 ng/mL (Treatment B) to 81.507 ng/mL (Treatment F). The mean concentration-time profile for Treatment A, the oral dose, differed from those of the other Day treatments by having a substantially lower mean peak concentration (mean Cmax of 1.863 ng/mL) and longer time to reach the peak (mean Tmax of 0.994 h).
The results of the dose proportionality assessment following deep-lung inhalation dosing for plasma dronabinol are detailed in the following figures: Cmax (
The mean (SD) pharmacokinetics parameters for 11-OH-THC after single dose dronabinol administration are presented in Table 6.
The mean (SD) pharmacokinetics parameters for 11-OH-THC after multiple dose dronabinol administration are presented in Table 7.
The results demonstrate that with the exception of Treatment B, the deep-lung inhalation treatments resulted in similar plasma 11-OH-delta-9-THC concentration-time profiles with rapidly reached peak concentrations and equally quick decline in post peak concentrations on both Days 1 and 5. For the five Treatments C, D, E, F, and G, the mean Tmax ranged from 0.115 hours (Treatment F) to 0.208 hours (Treatment C) on Day 1 (mean Cmax range of 0.614 ng/mL for Treatment C to 2.384 ng/mL for Treatment G) and from 0.084 hours (Treatment F) to 0.208 hours (Treatment C) on Day 5 (mean Cmax range of 0.466 ng/mL for Treatment C to 3.476 mg/mL for Treatment F). All subjects in Treatment B had OH-delta-THC concentration values below the 0.500 ng/mL limit of quantification.
The mean concentration-time profile for Treatment A, the oral dose, differed from the other treatments. Although the mean peak concentration for Treatment A (mean Cmax of 2.610 ng/mL) was similar to that of Treatment G, the time to reach the peak was substantially longer (mean Tmax of 1.5 hr) compared to those observed following the first doses of the five deep-lung inhalation treatments with concentration values above the Below Quantifiable Limit (BQL) measurement
The results show that with the exception of the 2.0 mg deep-lung inhalation dose level tested at the 53, 77, and 101 hour (P=0.01478), 11-OH-delta-9-THC was at steady state for the remaining dose levels at all the timepoints tested (P>0.05 for all treatments).
The results of the dose proportionality assessment for plasma 11-OH-delta-9-THC following deep-lung inhalation of dronabinal are summarized in
Comparison of the pharmacokinetic parameters of dronabinol and 11-OH-delta-9-THC following a single 5 mg oral dose of dronabinol given in Treatment A with the 6 ascending deep-lung-inhalation doses indicate that the inhalation doses were more rapidly and efficiently absorbed than oral dronabinol with a Tmax range of 0.03-0.5 hours. Equivalent AUC values to 5 mg oral dronabinol were obtained from an inhaled dose between 0.2 and 0.4 mg. In addition, the ratio of the 11-OH metabolite AUC to dronabinol AUC was about five times lower for the inhaled administration route when compared to oral delivery, indicating that oral dronabinol underwent more extensive first-pass metabolism than inhaled dronabinol.
Comparisons of the pharmacokinetic parameters between the first and last multiple deep-lung inhalation dose of each treatment showed no apparent differences in Cmax of dronabinol and 11-OH-delta-9-THC. However, T1/2el increased considerably between Day 1 and Day 5 doses, particularly for Treatments D, E, F, and G. Although for higher dose levels the values of mean AUC(111-135) were higher than the values of AUC(0-inf) for respective treatments, a direct comparison between these two parameters is not appropriate based on the design of this study. The observed increases in half-lives during repeated dosing with dronabinol may indicate insufficient assay sensitivity to detect the true elimination phase of the two analytes, what may lead to substantial accumulation of both the drug and its active metabolite with long term multiple dosing.
Results of dose proportionality assessments for the first and for the last multiple doses of dronabinol and 11-OH-delta-9-THC showed some statistically significant differences; however, there were no apparent patterns in these differences, with the one possible exception of Cmax values increasing less than proportionally for the 2.0 and 2.4 dose levels. Since at higher dose levels the remaining parameters appeared to be relatively dose proportional, assay sensitivity is the more likely cause of these apparent differences, rather than dose dependent kinetics.
Following the 5 mg oral dose given in Treatment A, the mean Cmax was approximately three fold smaller, the AUC values were comparable, and the mean Tmax was 33 times longer compared to the lowest, 0.2 mg, single-dose deep-lung inhalation of dronabinol given in Treatment B. Based on relative AUC(0-inf) vales, the 0.2 mg inhalation dose was about 20-fold more available than the oral dose.
However, the pharmacokinetics of the active metabolite, 11-OH-delta-9-THC, showed the opposite trend. The mean Cmax following Treatment A was higher compared to all the single- and multiple-dose deep-lung inhalation treatments, with the exception of the last multiple-dose administration of Treatment G, where the mean Cmax value was identical to that of Treatment A. Following Treatment B, all 11-OH-delta-9-THC concentrations for both the single and multiple dose treatments were below the BQL. These observations indicate that following oral administration dronabinol undergoes high first pass metabolism, which includes conversion to the 11-OH-delta-9-THC metabolite. Based on these data, oral first pass is about 6-fold more efficient than inhalation first pass.
The results of dose proportionality assessment for the first dose of the 6 deep-lung inhalation treatments indicate that Cmax and AUC(0-t) show evidence of not being dose proportional, whereas AUC(0-inf) is dose proportional. Results for dose normalized Cmax are particularly inconsistent and show no discernable pattern. For example, dose normalized Cmax for Treatment F statistically appears not to be different from dose normalized Cmax values from any other treatment. However, the overall trend in Cmax values seems to indicate that Cmax values increase less than proportionally at the 2.0 and 2.4 mg dose levels. The results of dose normalized AUC(0-t) are somewhat easier to explain, in that only Treatment B appears to be significantly different from the other treatments. The most likely reason is that the observed dronabinol concentrations following the 0.2 mg dose given in Treatment B quickly decrease to below the BQL, and consequently, once dose normalized, the AUC(0-t) for Treatment B appears to be significantly lower than that of the other, higher dose treatments. The apparent dose proportionality of AUC(0-inf) suggests no apparent dose dependent kinetic effects on total drug exposure following single dose administration of dronabinol within the 0.2 mg to 2.4 mg dosing range studied.
The results of dose proportionality assessment for the first doses of the 6 deep-lung inhalation treatments are not consistent with the results observed following the last dose of each multiple-dose regimen. Following multiple dosing the only statistically dose proportional parameter for dronabinol appears to be Cmax. However, even for Cmax, the mean values increase less than proportionally at the 2.0 and 2.4 mg dose levels, similarly to what was observed following the first dose of each treatment. While Cmin appears not to be dose proportional, this is due to dronabinol concentrations for Treatments B, C, D, and E declining to below the limit of quantification during the sampling interval; whereas for Treatments F and G they remained above the BQL. Since dose normalized Cmin values are similar for Treatments F and G, it is likely that Cmin is actually dose proportional, but that the current assay is not sensitive enough to detect dose proportionality for Cmin at all dose levels tested.
The issue of assay sensitivity becomes also a factor in evaluating the results of dose proportionality assessment for AUC(111-135) and Cavg, since we have defined Cavg as AUC(111-135)/24. It appears that Treatments B and C have a substantially lower dose normalized AUC(111-135) compared to Treatments D, E, F, and G. Generally, in case of dose-dependent kinetics, the opposite pattern would be expected. Evaluation of the concentration data collected for each subject during the Hour 111-135 sampling interval shows that no detectable dronabinol concentrations have been reported in any of the subjects beyond the Hour 113 sample for Treatment B and beyond the Hour 115 sample for Treatment C. For Treatments D and E, some subjects have detectable levels up to 123 hr, whereas for Treatments F and G, values remained above BQL throughout the sampling interval. Consequently, while based on these results the assessment of dose proportionality for dronabinol AUC(111-135), Cmin, and Cavg at all dose levels cannot be made, evidence from the higher dose levels suggests that no dose dependency exists for any of these parameters.
Results of dose proportionality assessment for 11-OH-delta-9-THC pharmacokinetic parameters following multiple-dose deep-lung inhalation treatments with dronabinol show that all the parameters were essentially dose proportional. However, the Cmax values also appeared to increase less/than proportionally at the 2.0 and 2.4 mg dose levels; a trend similar to what was observed for the parent compound. Treatment B was excluded from all comparisons due to all concentration values being below the BQL. For the remaining five treatments, the main effects were not statistically significant (P<0.05) for any of the 11-OH-delta-9-THC parameters following the last dose, and for Cmax and AUC(0-t) following the first dose of the deep-lung inhalation treatments. Although following the first dronabinol dose, the 11-OH-delta-9-THC dose normalized AUC(0-inf) for Treatment C was substantially lower than for Treatments D, E, F, and G, as mentioned earlier in this discussion, only 3 subjects in Treatment C had calculable AUC(0-inf). Since the extrapolated portion of their AUC(0-inf) varied from 95% for Subject 21 to 44% for Subject 17, AUC(0-inf) estimates cannot be considered accurate for this treatment. AUC(0-inf) was dose proportional for Treatments D, E, F, and G.
The design of the multiple dose portion of the study, where each of the 6 deep-lung inhalation dose levels was administered every 5 hours for 4 daytime doses, followed by a 9 hour nighttime interval prior to the next (morning) dose, with the pattern repeating until 12 consecutive doses were given, precludes a direct comparison between the AUC values on Day 1 and Day 5. The inconsistent intervals between doses results in both the drug and its metabolites not being at steady state during the sampling interval. Consequently, the comparison between steady state AUC(0-0), where 0 is the dosing interval, and single dose AUC(0-inf) cannot be made. Generally, for a drug which dose not alter its own kinetics with multiple dosing, the two AUC values can be expected to be the same.
Based on the Cmin values of 0 for both the drug (Treatments B through E) and 11-OH-delta-9-THC (all treatments), it can be concluded that little accumulation of either compound is taking place. In that case, a direct comparison between AUC(0-inf) values between the single and last multiple dose could be made for each treatment. However, due to questions of accuracy of extrapolation for AUC(0-inf), this comparison would be of limited value for the current data. Furthermore, since due to assay sensitivity it is possible that the observed terminal phase is the distribution and not the elimination phase, comparison of AUC(0-24) (single dose) with AUC(111-135) for multiple dose is also inappropriate. The disproportionate increases in AUC(111-135) compared to AUC(0-24) for a given treatment are more likely an indication of accumulation of the drug and metabolite in the plasma, as opposed to changes in pharmacokinetics of the two compounds with multiple dosing.
The reasons for suspecting that the observed half-lives are representative of distribution rather than elimination phase are twofold. First, while the observed half-lives for single doses of dronabinol are relatively similar for the 6 inhalation dose levels, for the multiple doses for Treatment D and higher they begin to increase disproportionately. For example, for Treatment G, the mean half-lives are 1.69 h for Day 1 and 20.6 h for Day 5. This suggests that at lower dose levels even following multiple dose administrations the true elimination phase may have been either completely missed or at least underestimated. Furthermore, at lower dose levels, the Kel intervals were also assigned over shorter time intervals due to concentrations decreasing to below quantifiable levels faster.
The second reason is that while similar trends can be observed for the 11-OH-delta-9-THC data, the increases in the half-lives following multiple dosing are not as dramatic as those observed for dronabinol. As a consequence, for Treatment G, for example, the mean half-lives are 2.04 h for Day 1 and 6.66 h for Day 5. Therefore, on Day 5, the half-life of the metabolite is significantly shorter than that of the parent compound—a situation which is kinetically impossible, and which suggests that even at highest dose level of dronabinol the observed terminal phase is still not the true elimination phase for the metabolite.
Evaluation of the effects of dronabinol and 11-OH-delta-9-THC on the chosen pharmacodynamic markers, pulse rate and conjunctiva congestion, have not shown any dose-related effects or any apparent variability between the subjects receiving placebo and those receiving dronabinol. For pulse rate, the actual evaluations for the first/single dronabinol dose were based on a predose and four additional postdose observations taken at Hours 0.83, 1.83, 3.83, and 47.25. Within the last (Hours 111-135) dosing period, pulse rate was evaluated only 3 times. Consequently, only maximum and minimum rates and the fluctuation index could be reported from these data. For conjunctiva congestion, only predose and Hour 5 assessments were made following Day 1 dosing, while the last assessment was made at Hour 111. No parameters could be determined from these data.
C. Pharmacodynamics and Safety
Values of pulse rate and conjunctiva congestion assessment scale were listed and summarized using descriptive statistics. Although compartmental and non-compartmental modeling was planned for the pharmacodynamic (PD) markers, insufficient data were collected for either type of modeling. No parameters could be calculated from the conjunctiva congestion scale due to insufficient number of observations. For pulse rate, the parameters were calculated from the pulse rate data collected following the single oral dose and first and last doses of multiple deep-lung inhalations of dronabinol.
Based on the protocol, changes in pulse rate and conjunctiva congestion were evaluated with respect to dronabinol and 11-OH-delta-9-THC blood levels. However, since the majority of pulse rate measurements and conjunctiva congestion assessments were taken on Days 3 and 4, and on Day 5 prior to the 111-hour timepoint, which signified the start of the actual dosing period of pharmacokinetic interest, only a general evaluation of the entire mean and individual pulse rate and conjunctiva congestion assessment profiles for each dosing period was possible.
Descriptive statistics were reported for vital sign measurements (pulse, sitting systolic and diastolic blood pressure, and respiration rate) by time of collection and change from predose for each treatment group. The last observation obtained prior to dosing (including rechecks) was used as the predose measurement. No postdose rechecks were used in summarization of vital signs.
Descriptive statistics were reported for changes from predose in conjunctiva congestion. The following cognitive assessments were listed by subject and summarized by timepoint of collection: Continuous Performance Test, Digital Symbol Substitution Test, Hand-Eye Coordination Test, Randt Picture Recognition Test, and Sedation Observation Rating.
Descriptive statistics were reported for changes from predose in pulmonary function test. The following pulmonary function test assessments were listed by subject: FVC (Forced Vital Capacity (L)), FEV (Forced Expiratory Volume in one (1) Second (L)), FEV1/FVC, FEF25-75%, and PFER.
1. Pulse Rate
Dose-related effects of dronabinol and 11-OH-delta-9-THC on pulse rate were assessed by reporting each subject's pulse rate values, in beats per minute (bpm), following the single and multiple dose administrations of dronabinol. The arithmetic means of parameters calculated from pulse rate values following single dose dronabinol administration for Treatments A through G are summarized in the Table 8.
The mean pulse rate versus time curves for these treatments are presented in
The results show that there was substantial variability in the pulse rates of all subjects in this study, however, no discernable pattern of change in pulse rates was apparent for any of the dose levels or for the comparison of first versus last dosing interval data.
The mean pulse rate parameters following the dronabinol dose on Day 5 of each of the 6 deep-lung inhalation treatments are presented in Table 9.
Since in addition to predose, only three pulse rate measurements were taken following the last deep-lung inhalation dose of each treatment, and since the last measurement was collected at 114.83 hours, no estimates of AUC(111-135) have been included for the pulse rate parameter tables. Similarly, following the first/single dronabinol dose, an insufficient number of pulse rate assessments were collected to accurately estimate AUC(0-t).
2. Conjunctiva Congestion
Dose-related effects of dronabinol and 11-OH-delta-9-THC on conjunctiva congestion were assessed by reporting each subject's conjunctiva congestion scores following the single and multiple dose administrations of dronabinol. Conjunctiva congestion was not assessed for subjects in Treatment A.
The mean conjunctiva congestion scores versus time curves for these treatments are presented in
No parameters could be evaluated from the conjunctiva congestion scale assessment, due to insufficient number of assessments performed following both first and last dronabinol dose. Following the first dose, and through the subsequent 48-hour pharmacokinetic sampling period, only two assessments were taken, one at predose (Hour 0) and one at Hour 5. Since the last conjunctive congestion assessment for all subjects in Treatments B through G was taken at Hour 111, essentially no conjunctiva congestion data was collected in the last dosing period of interest (Hours 111 through 135).
The majority of pulse rate measurements and conjunctiva congestion assessments were taken on Days 3 and 4, and on Day 5 prior to the Hour 111 timepoint which signified the start of the actual dosing period of pharmacokinetic interest. This scheduling of pharmacodynamic assessments presented a problem in fulfilling the protocol requirements for comparison between pharmacodynamic markers and blood levels of dronabinol and 11-OH-delta-9-THC since no blood levels were collected on those days. Consequently, only a general evaluation of the mean and individual pulse rate and conjunctiva congestion profiles for each dosing period could be performed. These showed no apparent differences in pulse rates or conjunctiva congestion levels between the single oral, and the single and multiple deep-lung inhalations of dronabinol. In addition, within each treatment group, there were no apparent differences between pharmacodynamic parameters of individuals receiving placebo and those receiving the actual dronabinol dose.
In conclusion, comparison of the pharmacokinetic parameters of dronabinol and 11-OH-delta-9-THC following a single 5 mg oral dose of dronabinol given in Treatment A with the 6 ascending deep-lung-inhalation doses indicate that the inhalation doses were more rapidly and efficiently absorbed. In addition, the greater dronabinol/11-OH-delta-9-THC ratios indicate that oral dronabinol underwent more extensive first-pass metabolism than inhaled dronabinol.
Further, comparisons of the pharmacokinetic parameters between the first and last multiple deep-lung inhalation dose of each treatment showed no apparent differences in Cmax of dronabinol and 11-OH-delta-9-THC. However, T1/2el increased considerably between Day 1 and Day 5 doses, particularly for Treatments D, E, F, and G. Although for higher dose levels the values of mean AUC(111-135) were higher than the values of AUC(0-inf) for respective treatments, a direct comparison between these two parameters is not appropriate based on the design of this study. The observed increases in half-lives during repeated dosing with dronabinol may indicate insufficient assay sensitivity to detect the true elimination phase of the two analytes, what may lead to substantial accumulation of both the drug and its active metabolite with long term multiple dosing.
Neither single nor multiple dose administrations of dronabinol had any apparent effect on pulse rate or conjunctiva congestion, and no apparent differences were discernable in these assessments between subjects receiving placebo and those receiving the active dronabinol treatments.
Dronabinol appeared to be generally well-tolerated up to the highest inhaled dose (2.4 mg). “Cough during dosing” was the most common AE reported during the trial. This cough was experienced by the majority of the subjects following the inhalation treatments, both active and placebo.
No treatment-related differences were observed regarding any physical examination, vital sign measurement, ECG, clinical laboratory result, pulmonary function measurement, or psychomotor performance test. Psychomotor performance evaluations demonstrated a reduction in sustained attention and motor reaction time, better coordination, a slowing of memory retrieval and reduction in executive function and speed of processing.
The above-mentioned patent and publications are incorporated herein by reference. While there is described above the principles of this invention in connection with a specific drug and specific semiaqueous solvents, it is to be clearly understood that this description is made only by way of example, and not as a limitation to the scope of this invention. For example, as a raw drug, synthetic or natural source-derived delta-9-tetrahydrocannabinol can be used, as well as prodrugs, isomers, derivatives, 20 metabolites, and the like. Generally a wide variety of hydroxy containing solvents can be used, such as isopropanol instead of ethanol and polypropylene glycol instead of propylene glycol, so long as they are pharmaceutically-acceptable. All such variations are within the full intended scope of the appended claims. The contents of all cited references throughout this application are hereby expressly incorporated by reference. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmacology and pharmaceutics, which are within the skill of the art.

domain: medical


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ANNOUNCING PANTONE 18-3838 ULTRA VIOLET, PANTONE® COLOR OF THE YEAR 2018.
A dramatically provocative and thoughtful purple shade, PANTONE 18-3838 Ultra Violet communicates originality, ingenuity, and visionary thinking that points us toward the future.
Enigmatic purples have also long been symbolic of counterculture, unconventionality, and artistic brilliance. Musical icons Prince, David Bowie, and Jimi Hendrix brought shades of Ultra Violet to the forefront of western pop culture as personal expressions of individuality. Nuanced and full of emotion, the depth of PANTONE 18-3838 Ultra Violet symbolizes experimentation and non-conformity, spurring individuals to imagine their unique mark on the world, and push boundaries through creative outlets.
Historically, there has been a mystical or spiritual quality attached to Ultra Violet. The color is often associated with mindfulness practices, which offer a higher ground to those seeking refuge from today’s over-stimulated world. The use of purple-toned lighting in meditation spaces and other gathering places energizes the communities that gather there and inspire connection.
What is the PANTONE Color of the Year?
A symbolic color selection; a color snapshot of what we see taking place in our global culture that serves as an expression of a mood and an attitude.

domain: artistic


Democratic mayoral candidates to debate on campus April 18
A view of the inside of ENR2 shows its unique construction and modern style. There will be several events being held in the building this semester including a Campus Conversation on Sustainability on Jan. 17 and the "Feeding your Genome" Conference Feb. 22-24.
The Pima County Young Democrats and University of Arizona Young Democrats will host a forum for Tucson’s Democratic mayoral candidates in the ENR2 Building Room N120 on Thursday, April 18, from 5:30-7:30 p.m.
With the retirement of Tucson’s current mayor, two-term Democrat Jonathan Rothschild, this year’s race is filled with candidates. Four local Democrats will face off in a primary election scheduled for Aug. 27. Two Republican candidates and a number of independents have also entered the race.
“The goal of UAYD and PCYD in hosting this event on campus is to help empower young people from all walks of life to have a say in the democratic process and to ensure that their voices will be heard,” said Adrian Sacripanti, director of media for the UA Young Democrats and a systems engineering student at UA, in an email.
Democratic candidates Randi Dorman, a downtown developer without previous political experience; Steve Farley, a veteran of the Arizona Legislature, and Regina Romero, a current councilwomen, all plan to attend the forum and answer questions submitted by students and community members through the event’s Facebook page.
The fourth Democratic candidate in this year’s primary election is Denny Crafton, who will not attend the forum.
Thomas Volgy, a UA professor in the School of Government and Public Policy and a former Tucson mayor, said he believes this year’s mayoral election will be focused around four key issues: income inequality and low wages, the quality of public education, the quality of community life (e.g. air quality and transportation) and the running of clean or publicly funded election campaigns.
“Tucsonans are far more knowledgeable about the problems in our community than politicians often give them credit for,” Volgy said in an email. “They want to see concrete, pragmatic proposals for the problems they face rather than symbols.”
According to Sacripanti, candidates will face questions around these issues as well as the state of the environment, education, gentrification and the concerns of immigrant communities in Tucson.
“The City of Tucson, like many other college towns, is going through a period of growth and development, especially around the university area,” Sacripanti said. “As a result, the issue of increased student housing and the effect it has on historic neighborhoods — especially downtown — has been placed into the spotlight.”
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2 edition of Pharmaceutical innovation found in the catalog.
N. E. J. Wells
|Statement||(researched and written by Nicholas Wells).|
|Series||Studies of current health problems -- no.74|
|Contributions||Association of the British PharmaceuticalIndustry. Office of Health Economics.|
|The Physical Object|
|Number of Pages||50|
This book explores four important issues in pharmaceutical innovations: (1) the industry structure of pharmaceutical innovation; (2) incentives for correcting market failures in allocating resources for research and development; (3) competition and marketing; and (4) public evaluation of the benefits and costs of innovation.3/5(2). Pharmaceutical innovation is an international enterprise. Although the United States is an important contributor to pharmaceutical innovation, we found that more than 20 countries contributed to the development of the NMEs with patents at the time of by:
1 A total of three hundred and nineteen new chemical entities (NCEs) were investigated in man for the first time between and by seven UK-owned pharmaceutical companies. The majority (%), were self-originated by the UK company or one of its Cited by: Supply may be global but demand remains national, structured by national health care, medical practice, and regulatory systems that do impact on innovation. Despite these criticisms, much is accomplished in this book. The pharmaceutical industry has been insufficiently studied across the world, more so in Europe than in the United States.
By reforming harmful supranational regulations, Thomas Pogge is developing a complement to the patent system to stimulate pharmaceutical innovations that would be accessible, without delay, to. This article investigates pharmaceutical innovation by analysing data on the companies that introduced the ∼1, new drugs that have been approved by the US FDA since Implications of this Cited by:
Specification for gauge blocks and accessories
optimal size of a bank
Poems in prose.
Reductive photo-dechlorination (RPD) process for safe conversion of hazardous chlorocarbon waste streams
The Arthur Avenue cookbook
Permian and Triassic of the southern North Sea
Landscape architecture uniform national examination
Energy and the city
Catalogue of the Ruskin Museum, Coniston Institute.
Principles of biology II
Confidential U.S. State Department central files.
Thought, action and intuition as a Symposium on the Philosophy of Benedetto Croce
Jennys Surprise Summer
Pharmaceutical Innovation concludes with a number of case studies that examine factors influencing the rate of drug development. The book-s resources also include a list of references for every chapter, an index, and a helpful by: Book Description This book reviews existing evidence and new ideas about how to best promote pharmaceutical innovation.
It covers specific topics such as the methods used to promote development of new vaccines, the drugs used to treat uncommon diseases, and the drugs for treating diseases that are prevalent in low-income : $ “The book remains the key important publication of pharmaceutical innovation for business executives, scientists and students.
The 3rd edition was updated especially regarding innovation alliances and addresses the key challenges that pharmaceutical R&D is facing nowadays.” (Katharina Caspary, Director Pharmacovigilance, Horizon Pharma)Author: Oliver Gassmann. Addressing fundamental questions in the field of pharmaceutical innovation, this book will appeal to scholars and practitioners in intellectual property, competition law and life sciences regulation, as well as pharmaceutical companies and by: 1.
This book explores four important issues in pharmaceutical innovations: (1) the industry structure of pharmaceutical innovation; (2) incentives for correcting market failures in allocating resources for research and development; (3) competition and marketing; and (4) public evaluation of the benefits and costs of innovation.
“Leading Pharmaceutical Innovation, Gassmann and colleagues describe the current status of the pharmaceutical industry.
This book comprises seven chapters, where each could be seen as a review of the addressed by: The book is based on the three most important challenges in pharmaceutical innovation: productivity dilemma, new technology trends, globalization and outsourcing Due to the CTO-roundtable with 14 selected international experts in pharmaceutical R&D whose result is presented, the book has a strong perspective from senior management.
Pharmaceutical giants have doubled their investments in drug development in the past decade only to see new drug approvals remain constant.
This book investigates and highlights a set of proactive strategies aimed at generating sustainable competitive advantage based on value-generating business practices. The Journal of Pharmaceutical Innovation (JPI) publishes in the areas of the pharmaceutical sciences such as drug development with a focus on manufacturing, process control, and technology, among many other subfields of research.
Applied Pharmaceutical Innovation. We’re bringing life-saving research to the real world. Applied Pharmaceutical Innovation. We’re working to bridge the gap in drug development. Book a consultation. Join us. commercial projects 0. Pharmaceutical innovations are currently guided by a patent system, the patent system protects the innovator of medicines for a period of time.
The patent system does not currently stimulate innovation or pricing that provides access to medicine for those who need it the most. It provides for profitable innovation.
As of about $ Billion is spent on research and development Author: YoungTae Seo, Dimitra Pappa, Pete Kingsley, Remco L. de Vrueh, Piergiuseppe Pusceddu. Pharmaceutical Innovations PI is sad to announce the passing of our founder, Gilbert Buchalter. "It is our mission to supply unique and superior products that are cost effective and manufactured to a standard of excellence unequaled in the industry." PRESIDENT OF THE UNITED STATES HIGHEST AWARD FOR EXCELLENCE IN EXPORTING.
Managing innovation in pharma Pharmaceutical industry perspectives on the Global Innovation Survey The insatiable appetite of society, investors and patients for pharmaceutical innovation is linked to the breakthrough advances in science and technology by the innovation process.
Managing small steps in that process can make a big Size: 2MB. Book review of “Pharmaceutical Innovation, Competition and Patent Law – A Trilateral Perspective”, edited by Max Planck Director Josef Drexl and Finnish scholar Nari Lee (Edward Elgarp., ISBN 0 7).
Authored upon request by European Competition Law Review (Sweet Maxwell). Title: The title should then followed by the author name and the institution name and address by indicating suitable superscripts.
An asterisk (*) must be placed after the corresponding authors name as superscript whose email id, fax, telephone number can be given. Corresponding author has the responsibility to ensure that all co-authors are aware and approve the contents of the. About the e-Book Pharmaceutical Innovation Pdf The pharmaceutical industry worldwide is a rapidly burgeoning industry contributing to growth of gross domestic product and employment.
Technological change in this field has been very rapid, with many new products being : Frank A Sloan. Journal of Pharmaceutical Innovation. From R&D to Market. Submission guidelines They should describe in detail new and innovative methods and techniques used by pharmaceutical professionals serving all aspects of the industry including manufacturing and applied pharmaceutical science and technology, process and product understanding and.
A new book offers a manifesto for how the pharmaceutical industry should function. Chris Pope. Ma He lauds pharmaceutical innovation as the engine of medical progress and offers suggestions for protecting patients from high prices while preserving the enormous investments that the industry needs to thrive.
Efficient Reward System for Pharmaceutical Innovation 3 innovator and the therapeutic benefit of the product.4 The current system makes the incentives for innovation dependent on this seriously dysfunctional market.
This book is motivated by these complex issues associated with pharmaceutical innovation and aims to communicate and disseminate the findings of research on this topic.
Early drafts of the chapters (except for the introduction and concluding chapter) were presented at the International Conference on Pharmaceutical Innovation held in Taipei.
Pharmaceutical Care in Digital Revolution is a practical resource to equip pharmaceutical care stakeholders, such as pharmacists, physicians, pharmacy technicians, and students as well as those in surrounding ecosystems like payers or regulators.
It is a crucial reference to understand how technological innovation is changing the paradigm in.Pharmaceutical giants have doubled their investments in drug development in the past decade only to see new drug approvals remain constant.
This book investigates and highlights a set of proactive strategies aimed at generating sustainable competitive advantage based on value-generating business practices. We focus on three sources of pharmaceutical innovation: Reviews: 1.Innovation Pharmaceuticals is a publicly traded biopharmaceutical company dedicated to discovering and advancing innovative medical therapies with dermatology, oncology, anti-inflammatory, and antibiotic applications.
Click here for a Corporate Overview.


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domain: travel


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Cloudiness will be increasing into Friday with a few showers possible by late Friday into Saturday morning. Colder air will return Saturday night into early next week with temperatures near freezing Monday morning.
Five crashes on, or near, Neches River Bridge on Sunday
DPS officials say five separate crashes on or near the Neches River Bridge caused a traffic backup on Interstate 10 that lasted hours Sunday.
The crashes involved 13 vehicles. It happened at about six o'clock Sunday evening.
Firefighters had to use the jaws of life to free one person who paramedics flew to a local hospital.
Others involved in the crash received minor to no injuries.
Officials say the five crashes were either caused by debris in the road or cars not slowing down or failing to stop.

domain: news


Processes are the lifeblood of any organization, yet their effectiveness often remains unexamined. Understanding the magnitude of process performance is indispensable for overall business success. Let's delve into the topic in-depth.
Importance of Measuring Process Performance
Process performance refers to the efficacy with which a business process accomplishes its intended function. It is an integral aspect of operational efficiency, linked inextricably to a company's profitability and growth.
Measuring process performance illuminates the pathway to continuous improvement, offering visibility into areas of inefficiency or underperformance. It aids in realizing organizational goals and strategies, fostering better decision-making, and driving growth.
Key Metrics for Evaluating Process Performance
Some of the key performance metrics include:
1. Efficiency. Efficiency is the ratio of output to input in a process. High efficiency signifies optimal resource utilization.
2. Effectiveness. Effectiveness measures whether the process is producing the intended results or meeting predefined objectives.
3. Cycle Time. Cycle Time refers to the total time from the beginning to the end of a process. A shorter cycle time is indicative of a well-optimized process.
4. Process Yield. Process Yield calculates the number of correct outputs divided by the number of total outputs. A higher yield suggests a more successful process.
Techniques to Measure Process Performance
How do we measure these metrics? The following techniques are widely utilized.
Process Mapping involves creating a visual representation of the process, offering a holistic view of the entire process flow.
Statistical Process Control (SPC)
SPC employs statistical methods to monitor and control a process, facilitating data-driven decision making.
Six Sigma Methodology
Six Sigma Methodology aims at reducing process variation and improving quality, typically leading to an increase in customer satisfaction and a reduction in cost.
Benchmarking involves comparing a company’s performance with industry best practices or competitors to identify areas for improvement.
Process Mining and/or Task Mining
Implementing Process Performance Measurement
Let's briefly outline the steps to implement process performance measurement in an organization.
- Define objectives: Start by establishing clear, measurable goals aligned with your organization’s strategy.
- Identify key processes: Determine the processes that significantly influence the achievement of these objectives.
- Establish metrics: Choose appropriate metrics that can effectively gauge process performance.
- Collect data: Ensure consistent data collection methods and that the data is accurate and timely.
- Analyze and act: Use the collected data to identify trends, make informed decisions, and implement process improvements.
In conclusion, understanding how to measure process performance is crucial for the operational efficiency and success of an organization. It is an ongoing process that requires the constant monitoring and reviewing of metrics, the implementation of improvements, and the adoption of a culture of continuous learning.
Keep in mind a balanced scorecard for process performance
A Balanced Scorecard is a strategic planning and management system used extensively in business and industry worldwide. It translates an organization's mission and vision into actual operational actions, spanning four main perspectives: Financial, Customer, Internal Process, and Learning and Growth.
Now, how does the Balanced Scorecard tie into process performance measurement? Here's why it's crucial:
- Holistic View: The Balanced Scorecard offers a comprehensive view of the business by considering four critical perspectives. This holistic approach ensures that process performance is not just judged on efficiency or output but takes into account customer satisfaction, financial results, and learning and growth initiatives.
- Strategic Alignment: By linking process performance metrics with strategic objectives, the Balanced Scorecard ensures that every process aligns with the organization's broader goals. It aids in prioritizing processes that contribute most significantly to strategic objectives.
- Cause and Effect Understanding: The Balanced Scorecard maps out the cause-and-effect relationship between different performance measures. This way, it helps identify which processes have the most considerable impact on the organization's performance and consequently need the most attention.
- Focus on Continuous Improvement: The Balanced Scorecard enables organizations to monitor progress over time and adjust strategies as necessary, fostering a culture of continuous improvement.
- Balancing Short and Long-Term Goals: By offering a balanced view of the performance, the scorecard helps in balancing short-term operational goals with long-term strategic objectives. It helps businesses understand the trade-offs they may need to make and ensures sustainability.
Remember, performance is the foundation upon which businesses are built. Therefore, making process performance measurement a part of your organizational DNA is imperative for sustainable growth and success.


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Pistol is the youngest child and only daughter of Pete and Peg and the little sister of P.J. At the beginning of the series, she is 4 years old and in preschool, but turns 6 at the end of the series and going into kindergarten. Pistol's name is generally considered to be a play on one of Pete's alias's in some classic cartoon shorts.
She is a kind daughter to Peg. She would usually bet with P.J. to see if their father would get angry if his expensive boats are destroyed or damaged by someone. She gets along with Goofy, Max and her big brother P.J. very well. She is an extremely energetic, hyperactive, adorable, feisty, mischievous, sweet, talkative, precocious and very beautiful little girl.
She has floor-length red hair tied in 2 pigtails with yellow ribbons, blue eyes, a black nose and wears a white long-sleeved blouse with a pink collar, sash and cuffs, yellow knee-length skirt, frilly red or white panties, pink ankle-length socks and white Velcro ballet shoes with pink trim.
TV Show Apppearnces
Pistol is generally a supporting character. Despite her cuteness, sweetness and beauty, she is often seen getting into messes, often having to be bailed out by Max and P.J. or even Pete. She often annoys P.J. into playing with her; however, the two are seen to work together sometimes.
- Neither Pistol nor her mother appear in the films, despite being based off of Goof Troop. One theory put forth by fans is that Peg and Pete divorced between the series and the first film, with the former taking Pistol with her.
- Japanese : Mika Kanai
- English : Nancy Cartwright
all information on Pistol Pete came from http://disney.wikia.com/wiki/Pistol_Pete

domain: entertainment


TPV360 addresses critical pain points for highly regulated businesses with the launch of a high-tech, intuitive, and low-cost (SaaS) third-party verification platform
Mississauga, Ontario, May 29th, 2020 – TPV360, a division of the well-established Customer Experience Technology Company and Global Contact Center Operator, ContactPoint360, Inc., has reimagined the third-party verification process from the ground up. The next generation TPV360 Third-Party Verification platform includes a cloud-based portal with accompanying mobile applications for Android and iOS.
The new TPV360 platform, designed by customer experience and compliance experts after decades of serving highly regulated industries, is purpose-built to fill critical gaps within the TPV process and provide solutions based on input from TPV360 subject matter experts, the in-house software development team and scores of clients over the years. The system, loaded with intuitive features, is quickly adopted by clients, BPOs, and consumers across the entire transactional ecosystem. TPV360 has included multiple levels of automated security protocols for telesales, retail/kiosk sales, door to door sales via live agent or self-verification through SMS link or email.
Key Features: The best feature sets all under one roof.
Some key features include identity checks, multifactor authentication via phone, email and SMS, geo-tracking, credit evaluations, remote recording capability, fraud alerts for management, electronic contracts, and e-signatures with versions that facilitate all aspects of the verification process. Realtime dashboards keep clients, vendors, and agents up to speed with dynamic reporting via customizable permission-based access.
“We’ve been in the customer experience sector for well over a decade now. Over the last year, our TPV360 project team has interviewed key stakeholders, including clients, vendors, compliance authorities, and consumers, to make sure we thoughtfully considered and fine-tuned every touchpoint in the system during development”, said Asad Mirza, CEO, and Founder of TPV360 and its parent company, ContactPoint360. Inc.
The TPV360 approach takes into account all users that interact with the system and goes the extra mile to ensure that each interaction provides an efficient and user-friendly experience and most importantly, results.
Clients within highly regulated industries like energy, healthcare and finance need to drive revenue or finalize transactions in a compliant manner. They need to verify whom they are doing business with and if the consumer meets specific predetermined criteria. These clients must have measures in place to make sure internal or external salespeople are operating within company policies and governmental guidelines.” All data across multiple vendors is protected by state-of-the-art security measures and is easily accessible by approved client stakeholders in real time via dashboard reporting.
Sales Departments and Outside Vendors: This group must be empowered with tools that make the sales process as streamlined as possible. They need to see where they are against goals or sales quotas at any given time. Whether they are selling on the phone, at a retail location, or door to door, TPV360 provides agents, and sales managers need to know info via the web or mobile interfaces. Mangers responsible for monitoring performance get real time reporting via our online portal and supplied with red flag alerts to possible behavioral or compliance violations.
Consumers: The first impression of a new customer is extremely important. If identity checks out, the sale is compliant and closed, it must still be verified by an objective third party within highly regulated industries. This can be frustrating for consumers as they just went through an entire sale pitch and agreed to the offer. TPV360 makes this critical stage of the process easy by providing many options. Traditional voice verification, email, SMS are all available depending on local regulations.
“We are disrupting the space through a combination of efficient and agile software development, robust feature set offerings, competitive pricing and a problem-solving mindset “, said Mark Rodrigue, SVP Operations and Global Growth for TPV360 and ContactPoint360. Inc.
The mission of TPV360 is to offer a more holistic service so clients can get the best technology available all under one roof along with new proprietary solutions filling critical gaps that have existed in the marketplace for many years.
Third party verification is a must have for many industries. TP360 has developed a service that is designed to satisfy stakeholders across the board from Compliance, IT, Legal, and Operations. CFOs and accounting are delighted with our straightforward and competitive pricing model.
Seeing is believing. Contact us today for a live demo of the system. We would love the opportunity to show you how our world technology can drive revenue, increase efficiency and mitigate costs.
For sales information please contact Adrian Barry, Senior Sales Engineer by phone at 832-930-4343
Or email at firstname.lastname@example.org
Founded in 2019, TPV360, a division ContactPoint360, Inc. is a Service as a Software (SaaS) provider offering end-to-end third-party verification solutions via a next generation cloud-based platform and mobile applications for Android and iOS. Our encrypted cloud-based platform and mobile application solutions, enable multiple types of third-party verification, including telesales, door-to-door, and kiosk/retail sales efforts. TPV360 provides multiple layers of fraud protection and compliance-related tools to mitigate risk. At the same time, our cloud-based system and mobile apps help drive sales through a clean and intuitive user interface that enables salespeople to enter data more efficiently and close more accounts. TPV solutions are designed for highly regulated industries such as energy suppliers, utilities, healthcare (payer and provider) and banking/finance.
Founded in 2007, ContactPoint360 (www.contactpoint360.com) is a Canadian global customer experience company with contact center locations across North America, South America and Asia. The company provides business process outsourcing (BPO), multichannel customer experience solutions including voice, email, chat and social media. ContactPoint360 services major international clients across a variety of business sectors including energy, finance, retail, telephony and healthcare.


|Single Reduced||Double Reduced||Tin Coated Sheets|
|Gauge (inches)||0.0077 thru 0.0149||0.0060 thru 0.0118||0.0150 thru 0.0250|
|Width (inches)||20 thru 40||20 thru 40||20 thru 40|
Tin coating weight is expressed in pounds per base box and represents the total of tin coating on both sides with the exception of differentially coated tin plate.
Differentially Coated Tin Plate: A product having one surface more heavily tin coated than the opposite. The designation number is expressed by showing the two tin coating weights separated by a slash mark. The first number designation will represent the coating weight on the outside of coil or the top surface of cut sizes. In order to distinguish material having differential coatings, the side with the heavier coating is normally marked. By arrangement, a special marking can be supplied on the light coated side.
Coating Weight lb/bb
Tin Coating Weight
(per side) lb/bb
*The minimum spot value shall be not less than 80% of the minimum average coating weight.
Reflow is a 100% solid state induction heated process that provides an instantaneous change in surface of the tin plated steel from matte to mirror.
Bright Finish (melted): This is a high luster mirror like tin finish that results from an in-process melt and quench and is similar in appearance to the familiar hot dipped tin plate. Because of its strength, corrosion resistance, and mirror finish it finds wide acceptance for tin cans, crown caps, bottle tops, kitchen utensils, toys, electrical and electronic parts.
Matte Finish (unmelted): This is a grey-white and semi-lustrous finish that comes from the plating bath. It serves as an excellent base for paints, enamels, and lithograph applications. It can be soldered readily and formed on high speed equipment.
A chemical treatment is normally applied to the surface of tin plate. The purpose is to stabilize the surface to prohibit the growth of tin oxide on the surface, to prevent discoloration during soldering, and to prevent poor adhesion of lacquers used in tin can manufacturing.
Cathodic Sodium Dichromate (CDC) Treatment: This treatment is applied using a sodium dichromate solution with an applied current. This treatment provides a highly passivated surface against the formation of tin oxides. The aim range is 350 to 650 ug of chromium/ ft2 of surface area.
Sodium Dichromate Dip (SDCD) Treatment: This treatment comprises a simple dip through a sodium dichromate solution without any current. This treatment provides moderate passivation resistance to tin oxide. The aim range is 150 ug of chromium/ ft2 of surface area.
Electrolytic tin plate normally carries a very thin coating of oil to facilitate the separation of the wraps of a coil to prevent damage and to aid in customer processing. The oil is applied electrostatically in a range of 0.17 gms/ bb. The type of oil used is ATBC (acetyl tributyl citrate).
Eye Vertical: The coil is stretch wrapped to a skid.
Eye horizontal: The coil is stretched wrapped without a skid.
Ohio Coatings ships coils by truck, rail, or barge.


Digital pressure gauge is highly on demand in industrial sectors which require the gauging of pressure for proper performance and maintenance of their devices and machineries. Nowadays, the marketplace is full of digital pressure gauges that come with a variety of features and use advanced technologies for offering accurate and precise results. However, it will always be preferable to purchase them from well-known brands which provide quality performance. A few of the popular brands of digital pressure gauge range are:
Ashcroft digital pressure gauge:
Ashcroft is a leading manufacturer of Torque Calibration Commerce. The newest models out of this brand offer unmatched accuracy specifications of .05% full scale including linearity, repeatability, and hysteresis and temperature compensation from to 150° F. and you need not concern yourself with safety issues while using the the digital gauge range between the house of Ashcroft because they are FM approved for intrinsically safe operations, as well as are Class 1, Division 1, CE and CSA approved. It is going to be mentioned here that almost all the Ashcroft precision digital test gauge has 9 selectable units of measure and 7 different languages. All the digital gauges from this brand are
Sensocon digital pressure gauge:
The Sensocon is really a well known manufacturer of pressure gauge that is included with wonderful features and performance to accommodate the specifications of virtually all industry sectors. Features include selectable engineering units, digital calibration, direct flow and velocity reading, digitally scaleable 4-20 mA output, and many more. Sensocon pressure gauges are used for monitoring air pressure on compressors, checking tire pressure, monitoring liquid pressures in closed systems, a number of pharmaceutical applications, in addition to petrochemical, semiconductor, as well as other general process applications.
Get branded digital pressure gauge varieties online:
You can get these digitalized pressure gauges directly from the producer or you can also get both brands of digital gauge varieties online from the certified distributors of Instrumentation, Controls, and Gauges. This is to ensure that you get the best products within the best prices available. Moreover many of these online destinations come with dedicated customer support team that can help you in obtaining the most effective digital gauge that are suitable for your special application requirements. Besides all these, in addition, you get the main benefit of getting the product right in your doorstep, and this too by ordering through the comforts o your home or office with just the click of the mouse.
A digital pressure gauge is a vital measuring tool that is used to measure pressure. They have different specifications today and they are significantly better than mechanical gauges. However to suit your individual requirements, it will always be better to go through an effective checklists and obtain the best results.
Performance specifications of digital pressure gauges:
The simplest way to pick the digital pressure gauge for yourself is to look out for the ones that possess performance specifications of your requirements. You will find differences when it comes to maximum allowable pressure, accuracy, vacuum range, and operating temperature that have to be considered while ordering an electronic digital pressure gauge for yourself. Also lzkvat for your accuracy grade before zeroing on the one of the choice and requirement. It is only the main difference involving the true value and also the indication expressed as percent of the span. This can be denoted with a lettered grade. A number of them feature ASME B40.1 and DIN accuracy grades, or list the biggest reported percentage error.
Additional features of digital pressure gauges:
The huge interest in pressure gauge varieties in different industrial areas has resulted in the advent of newer versions with added features. Actually, these have undergone many changes since their invention. So, while ordering these gauging instruments always ask for ones with newer specifications like temperature outputs, temperature compensation, alarm switches, and output switches which can be compatible with transistor-transistor logic (TTL). They are however optional features, it is possible to opt for them as per your requirements. Some even come with negative pressure outputs for devices that measure differential pressure as in a digital Hand Tools Calibration Commerce.


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Hands down, the best LQ. Requested a rollaway bed online when ordered, got a call the next day stating that the rollaway isn't compatible with my room and gave me a better option...wow, most places don't even care about that stuff until you check in....更多
Chose the king suite because it was only $9 more a night. The room was huge. Living room with pull out sofa, chair with foot rest, desk with chair, coffee table, tv, refrigerator and microwave. Separate bedroom with King bed and tv. Each room had...更多
來自 拉昆塔胡桃木套房飯店Director of Sales LaQuintaHickory 的回應
Thank you for your kind words! It means so much to know that we are making the right choices when...更多
Very clean and comfortable hotel but the WOW factor was breakfast. Made to order eggs and omelette plus a wide variety of other items was a very nice surprise. I would definitely stay again. The front desk clerk was extremely polite and friendly. Rooms are...更多
Don't usually stay at this chain, but decided to try it. Very friendly staff and good breakfast offered. The rooms however are in serious need of upgrades and chair upholstery had quite a few nasty stains.
Hi Beth A,
Good afternoon, our breakfast is a hot buffet served each morning. Since I am not an expert on gluten free, I will tell you what our breakfast serves. Eggs made-to-order, or omelets if you prefer, with multiple... 更多
Hi Beth A,
Good afternoon, our breakfast is a hot buffet served each morning. Since I am not an expert on gluten free, I will tell you what our breakfast serves. Eggs made-to-order, or omelets if you prefer, with multiple choices for add on ingredients such as; spinach or mushrooms. Bacon and sausage are served on the buffet, along with biscuits, gravy, and breakfast potatoes. We also have, boiled eggs, pancakes, and waffles. Cold cereal, oatmeal, grits. and muffins are also easy to go options.


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It was while teaching history at the Wings Academy in the Bronx, that DonorsChoose.org founder and Chief Executive Officer Charles Best realized not all schools in America are created equal.
“Where I went to high school we went on field trips, we had graphing calculators for trigonometry, we had the supplies to do just about any art project; we did not want for anything,” recalled Best. “But in the Bronx, my colleagues and I would spend a lot of our own money on copy paper and pencils, and I thought, ‘There must be people who would love to help us – if they could see where their money was going.'”
On Monday, Aug. 27, during the annual Convocation Ceremony, Best recalled that initial spark that led him to create the non-profit organization DonorsChoose.org in 2000. Through the donations of 800,000 people across the country, DonorsChoose.org has provided more than $100 million in books, supplies, field trips and technology to teachers and their students at over half of the public schools in America.
Initially investing his own money to create a rudimentary site, Best asked his fellow teachers at Wings Academy to go to the fledgling DonorsChoose.org and ask for funding for a dream project. A health teacher needed “Baby-Think-It-Over” dolls for a pregnancy prevention course, an English teacher needed SAT prep books -eventually hundreds of projects from across the Bronx had been posted.
With the help of Best’s students, who worked after school on a letter writing campaign, more than $30,000 in project funding was raised. More than a decade later, DonorsChoose.org has “delivered books, art supplies, field trips and technology to more than five million kids from low income families,” Best said. “I never thought I would be sharing numbers like that.”
In closing his Convocation address, Best invited those in attendance to make a difference in the lives of students; each attendee was given a $10 gift card to DonorChoose.org. “I am putting the ball in your court,” explained Best. “Find a project that really speaks to you, and think of those students beginning their school year, as you begin your adventure here. Know that you made those students’ first day of school just a little bit brighter.”
In recognition of Best’s dedication to public education and bettering the world of millions of children across the country, Best was given the prestigious President’s Medal on behalf of Gearan and the Hobart and William Smith Board of Trustees.
As a response to Best’s impressive work and thoughtful words, Gearan issued to students one charge for the academic year: “Ask what you can do.” A simple, yet immense call to action that ushers in a year dedicated to citizenship and community.
“As we engage one another as a community, thoughtfully consider the broader challenges and opportunities that face American higher education today,” Gearan urged, touching upon issues of sustainability, community engagement and inclusiveness. “With focus and determination, with the hard work of students, faculty, staff and our Board of Trustees working together, we can advance the College in notable ways.”
Board Chair Maureen Collins Zupan ’72, P’09 welcomed students, faculty and staff on behalf of the Board of Trustees. “You have before you two semesters to explore new concepts and cultures, to learn about the world and about yourself, to push your limits and expand your horizons,” remarked Zupan.
Student Trustee Kees Nordin ’13 reflected on community service, and making an impact on the world, while Student Trustee Loren Marshall ’13 reminded students that they are not visitors in Geneva – it is their home and they are a part of the city.
Provost and Dean of Faculty Titilayo Ufomata addressed the HWS community during her first Convocation, speaking to the duties of the faculty and the obligations to educate students as well as colleagues and themselves.
“To me, being good citizens of our community demands that we develop good instincts,” Ufomata said. “It demands that we recognize unintended consequences of our actions, that we think about others when advocating for ourselves and our units; and that we behave and feel beyond our own circumstances for the good of others.”
Other speakers included Professor of Philosophy Scott Brophy ’78, P’12, who served as the Faculty Marshall, and Associate Professor of Art and Architecture Michael Tinkler.

domain: sociology