text:
US6994842B2 - Aerogel powder therapeutic agents - Google PatentsAerogel powder therapeutic agents Download PDF
- Publication number
- Authority
- Grant status
- Grant
- Patent type
- Prior art keywords
- aerogel
- particles
- powder
- drug
- method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carier particles
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
This application claims benefit of 60/257,436, filed Dec. 22, 2000.
The present invention is directed to an improved method of delivering pharmaco-therapeutic agents in which the time required for drug delivery into a patient's blood stream is substantially reduced. The delivery is direct to the blood stream, but non-invasive, non-disruptive, and pain-free. Examples of the classes of pharmaco-therapeutic agents which may be delivered in accordance with the present invention include such as: opioid-receptor agonists/antagonists, dopamine-receptor agonists/antagonists, serotonin-receptor agonists/antagonists, monoamine transporter agonists, antimanic agents, anti-smoking agents and immunogenic therapies (antibody products to reduce peripheral levels of drug substances), vaccines, antibiotics, high blood pressure drugs, heart medications, asthma medications, sexual dysfunction medications, analgesics, anesthesia drugs, insulin, and the like.
There are four general types of drug delivery currently available: oral, injection either intravenous, subcutaneous or transdermal, implants, and inhalation. Each of the methods has advantages and disadvantages.
1. Oral administration is acceptable in most cases except that the drug delivery rate is often too slow and it can cause digestive tract upset.
2. Intravenous injection is effective, but is intrusive, painful, has a danger of causing adverse reactions from the body due to a high concentration drug flowing through one small pathway, and presents a danger of infection both for the patient and the health-giver alike. Also if the injections have to occur frequently, such as once or twice a day for insulin as an example, there is a problem of running out of injectable locations let alone pain, bruises and danger of infections. Transdermal injection can be an answer to a lot of problems but has not been widely used. The technology is still in early stages of development.
3. Implants are used to avoid multiple shots and to maintain constant dosage over a long period of time, but requires invasive surgery.
4. Inhalation is an ideal drug delivery method. It can be done widely and conveniently because it is very fast and non-intrusive. Inhalants such as for asthma have shown a lot of promise but they are still not completely satisfactory. They take effect very rapidly, sometimes even faster than intravenous injection, but the inhalant method is currently limited to a few medications due to the difficulties of forming suitable dispersions for delivery into the lungs. Also most inhalants today use a chlorofluoro compound (CFC) as a dispersant and there is a movement to move away from CFC's for environmental reasons as well as suspected harmful effects that CFC's might have inside the body.
The development of the first pressurized metered dose inhaler (MDI) in the mid-1950s was a major advance in the administration of drugs locally to the lung, especially for the treatment of asthmatics. More recently, research has focused on using the lung as a conduit to deliver biomolecules such as peptides and proteins to the systemic circulation. Sophisticated dry powder inhaler (DPI) and metered solution devices have also been designed, both to improve deep-lung delivery and to address the MDI actuation/breath coordination issue that is problematic for certain patients. Relatively little development effort has been applied to improve pulmonary drug delivery by means of new formulation strategies.
One attempt to produce an improved inhalant drug delivery system is that of Alliance Pharmaceutical which is based upon "PulmoSpheres" which are prepared by mixing a drug and a surfactant to form an emulsion and then spray-drying the emulsion to cause the drug to be encased in the shells of hollow, porous, microscopic surfactant spheres. The resultant powder is then suspended in a fluorochemical or other propellant or carrier for delivery of the drug medications into the lungs or nasal passages of a patient. The hollow/porous morphology of the microspheres allows non-aqueous liquid propellants such as fluorochemicals to permeate within the particles, improving suspension stability and flow aerodynamics while impeding particle aggregation. U.S. Pat. No. 6,123,936 utilizes this technology to produce a dry powder formulation for interferons. Use of the spray-drying process precludes the preparation of products from any heat-sensitive pharmaceuticals since the drying must be conducted at elevated temperature, i.e. about 50 to 200° C. (122–392° F.)
Moreover, the densities of porous particles that can be produced by a spray-drying process, although much lower than many currently available solid or liquid inhalant particles, are still too high for many uses resulting in too much of the drug which is being delivered not reaching the lung surfaces.
The porosity and surface area of the aerogel products of this invention are much higher than those of spray-dried particles. The density of the aerogel products, which can be as low as about 0.003 g/cc, is much lower than both the PulmoSpheres (about 0.1 g/cc) and that of crystalline powders (about 1 g/cc). As a result, the aerogel inhalants of this invention float much longer resulting in more pharmaceutical material reaching the inner part of lungs. Thus the delivery efficiency is improved.
Although the primary intended use of aerogels heretofore has been in the field of insulation, some inorganic oxide aerogels have been used as carriers for the delivery of agricultural, veterinary medicines, and pharmaceuticals. For example, Australian Patent 711,078 discloses the use of aerogels prepared from inorganic oxides like silica by surface modifying them for hydrophobicity and then use as carriers in agricultural and veterinary medicine, i.e. to carry an active material such as insecticides, nematicides, etc. as well as viruses, bacteria, and other microorganisms. Australian Patent 9965549 discloses the use of inorganic aerogels as carriers for pharmaceutically active compounds and preparations as solid, semisolid and/or liquid oral preparations.
None of the prior aerogels and uses thereof are related to aerogel particles which are soluble in pulmonary surfactant or the use of such particles as a dosage form for delivery of a pharmaceutical by inhalation as in the present invention.
It is an object of this invention to substantially increase the applicability of inhalation drug delivery to wider class of drugs by producing them in the form of aerogel powders.
It is a further object of this invention to formulate an aerogel powder form of a drug so that it is capable of reaching much of the available mucous area inside the lungs.
It is a further object of this invention to formulate an aerogel powder form of a drug for quick dissolution and introduction into the blood stream of mammals and quick release of the drug.
It is a further object of this invention to formulate an aerogel powder form of a drug for quick introduction into the blood stream of mammals and controlled release of the drug thereafter.
It is a further object of this invention to formulate an aerogel powder form of a drug for a long shelf life by making it physico-chemically stable in its composition and packaging.
It is a further object of this invention to produce devices and equipment suitable for delivery of an aerogel powder form a drug.
It is a further object of this invention to produce a controlled drug administration environment, e.g. room, in which drug delivery may be done passively, without coercion, man-handling, or intrusive measures.
This invention is directed to an aerogel powder form of a pharmaco-therapeutic agent for use as an inhalant for mammals including humans.
More specifically, in one embodiment the invention involves preparing highly porous, low density, micron sized aerogel particles directly from the therapeutic substance of interest as an inhalant. In a second embodiment, wet ultra-fine porous gels are prepared from a material which is soluble in pulmonary surfactant, if necessary the solvent used to prepare the wet gels is exchanged for a solvent in which the therapeutic agent is dissolved, then a solution of the therapeutic agent in a solvent is penetrated into the pores of the wet gel by soaking until the desired deposition occurs, and the aerogels formed by supercritical drying. In both embodiments the resulting aerogels are then milled to the desired final particle size.
The aerogel particles of the present invention exhibit a low density (down to about 0.003 g/cc), an extremely high porosity (up to about 95%), a high surface area (up to about 1000 m2/g) and a small particle size (micron sized and below). As a result of these properties, a pharmaceutical in the form of an aerogel powder results in a non-invasive high rate drug delivery system. The aerogel powders are in the form of extremely light, ultra-fine particles which will be easily airborne for an extended time during inhalation before settling down by gravity. This enables them to reach the innermost alveoli of the lungs and deliver the drug into the blood stream very rapidly.
The inhalable aerogel particle drug delivery method of the present invention is applicable to the preparation and use of inhalable forms of common therapeutic drugs such as insulin, aspirin, Viagra®, asthma medication, cold medication, antibiotics, etc. The drugs are delivered into the blood stream of a patient at a delivery rate well exceeding the drug delivery rate of intravenous injection and without the sting of a needle. The aerogel particle method bypasses potential problems with the digestive system and enables the medication to take effect at a much faster rate than is possible today.
Examples of substances that can be produced in the aerogel form of the present invention include but is not limited to: methadone, Orlaam®, Buprenorphine®, nicotine, other opioid-receptor agonists/antagonists, dopamine-receptor agonists/antagonists, serotonin-receptor agonists/antagonists, monoamine transporter agonists, anti-manic agents, anti-smoking agents and immunogenic therapies (antibody products to reduce peripheral levels of drug substances), vaccines, antibiotics, high blood pressure drugs, heart medications, asthma medications, sexual dysfunction medications, analgesics, anesthesia drugs, diabetic medications, and the like.
Particularly suitable substances are those useful in drug treatment programs. Methadone, a synthetic narcotic, which has been used for more than 30 years to treat heroin addiction by suppressing withdrawal symptoms and curbing the craving for heroin is particularly suitable. It is moderately soluble (12g/100 mL) in water, the preferred dosage vehicle since the mucous membrane transfers water to the particle on contact. Orlaam, another synthetic narcotic known generically as levomethadyl acetate, was approved in 1993, but has not been widely used. Buprenorphine, also a synthetic narcotic, is awaiting approval from the U.S. Food and Drug Administration for use as an anti-addiction drug. It causes weaker narcotic effects. No serious side effects are reported for any of the above three synthetic narcotics except for occasional constipation, nausea and dry mouth for some patients. Also, high dosages for all three were found to be much more effective in controlling the heroin addiction than low dosages.
Naltrexone is used to reduce alcohol cravings and to cause drinking to be less pleasurable (by inducing an unpleasant side effect such as nausea when ethanol consumption occurs). Naltrexone is a narcotic antagonist, which was originally used for narcotic dependency. Ethanol supposedly stimulates the body's natural opiates, and Naltrexone (or Revia) blocks this stimulation reducing cravings and pleasure. Naltrexone is only effective for 24 hours, thus a once daily dose is required. The pharmacokinetic efficacy of the drug is limited due to relatively slow absorption, thus making an alternative dosage to the solid pill form to deliver the drug rapidly to the bloodstream would have advantages.
Methadone and Naltrexone will be used as examples in the following description of how to prepare aerogel products of this invention. The aerogel forms of both drugs are sufficiently physicochemically stable to ensure adequate shelf life.
In general, the production of aerogels involves a sol-gel process during which a wet gel containing the substance of interest is formed with a proper solvent and catalyst. After the wet gel with nano-size pores and a lattice structure has been formed, a supercritical extraction process is used to supercritically dry the gel while avoiding potential collapse of the delicate pore and lattice structures due to the lack of surface tension of the supercritical fluid. Most commonly the supercritical fluid will be carbon dioxide (CO2). The resulting dried gel exhibits nano-size pores (generally about 1 to 100 nm, preferably about 5 to 50 nm, more preferably about 10 nm), a high surface area (generally about 100 to 1,500 m2/g, preferably about 100 to 1,200 m2/g, more preferably about 500 to 1,000 m2/g), a low density (generally about 0.1 to 0.0001 g/cc, preferably about 0.01 to 0.001, more preferably about 0.003 g/cc), and a small particle size (generally in the range from submicron up to about 2 microns).
Methadone hydrochloride is a synthetic narcotic analgesic commonly used to treat heroin addicts who would otherwise suffer narcotic withdrawal symptoms. Treatment consists of oral dosages of the soluble hydrochloride salt, which can be safely autoclaved for sterilization. The "free base" methadone has the chemical structure shown below on the right. It is likely to be the therapeutic agent, but is not water soluble. However, it is very soluble in non-polar organic solvents and fats, and should have appreciable solubility in liquid or supercritical carbon dioxide. The basicity of the molecule allows it to be readily protonated by strong acids to form an ammonium salt. The preferred form for handling is in the form of the ammonium salt, typically either as the hydrochloride shown on the left or as the sulfate (not drawn).
The salts do not have appreciable solubility in non-polar organic solvents, but rather have excellent solubility in water and alcohols (one gram of the hydrochloride salt dissolves in 0.4 mL of water, 3.2 mL of cold water, 2 mL of hot ethanol, or 12 mL of chloroform).
The methadone aerogel powder may be formed by co-gelling the free base with glucose (which is preferably formed in situ from diisopropylidene glucose precursor and sacrificial 1,2-diols via a trans-acetalization reaction) in a solvent by the addition of a stoichiometric amount of anhydrous hydrogen chloride or hydrochloric acid. Varying the ratio of methadone to glucose in the solvent will allow control of the gelling behavior of the hydrochloride salts to produce desired physical characteristics while avoiding the formation of a dense methadone hydrochloride crystallization. If desired, the anion can be changed and/or other acids may be used to modify wet gel formation when reacted with the methadone/glucose precursor/solvent combination. Examples of suitable acids include mineral acids (hydrochloric, sulfuric, nitric) and organic acids (gluconic, malic, fumaric, citric). The variables that can be used to control the gelling reaction are solvent identity, 1,2-diol identity (e.g. 1,2-phenyl-ethanediol, 1,2-propanediol, glycerol), methadone concentration, acid identity, temperature, percentage of water present, and the like.
Supercritical drying of the gels with carbon dioxide gives aerogel powders with the highest possible surface area. The supercritical drying process may be performed in any well known conventional manner. Thus further details of the supercritical drying process are not provided herein. The supercritical drying is performed at a temperature below about 40° C.
Naltrexone aerogel powder in accordance with the present invention may be produced in the following manner. Generally, Naltrexone is provided in the form of a hydrochloride salt to improve solubility in water and hence bioavailability. The formation of a high surface area Naltrexone containing aerogel powder will be accomplished by co-gelling the hydrochloride or other suitable salt of the free base Naltrexone with glucose in a similar manner to that described above for methadone. The glucose gel will preferably be formed in situ from a solution of 1,2:5,6 di-O-isopropylidene a-gluco-furanose and an excess of sacrificial 1,2-diols via acid-catalyzed trans-acetalization in an appropriate solvent. The resulting product will have Naltrexone suspended in a glucose/solvent gel matrix. Subsequent drying with supercritical carbon dioxide will provide the high surface area aerogel powders. Varying the ratio of Naltrexone to glucose in a particular solvent will enable control of the gelling behavior of the hydrochloride salts to avoid dense Naltrexone hydrochloride crystallization. The anion can be changed as well, and a variety of acids can be investigated which may enhance wet gel formation when reacted with the Naltrexone/glucose precursor/solvent combination. Mineral acids (hydrochloric, sulfuric, nitric) and a modest sampling of organic acids (gluconic, malic, fumaric, citric) may be used. System variables that can be used to control gelling behavior include solvent identity, 1,2-diol identity (e.g. 1,2-phenylethanediol, 1,2-propanediol, glycerol), Naltrexone concentration, acid identity, temperature, percentage of water present and rheological control additives. Supercritical drying of the gels with carbon dioxide will give aerogel powders with the desirable properties specified above.
The free base is highly soluble in supercritical carbon dioxide but not that soluble in water. In case, a slower and longer duration release of the drug is desired, then the aerogels can be prepared using free base Naltrexone. In such a case, aerogelized free base Naltrexone can be prepared by adsorbing it onto a preformed appropriate aerogel, e.g. glucose, while in the supercritical CO2 or other drying gas. This will be followed by depressurizing the system strategically to reduce the solute solubility and deposit the solute Naltrexone on the pores of the gels. Upon contact with pulmonary surfactant present on a patient's lung tissue, the glucose aerogel powder doped with the Naltrexone free base will dissolve rapidly, leaving behind tiny packets of free base Naltrexone directly on the lungs. The packets of these insoluble agents are so small that they simply diffuse across the membrane into the blood stream at a desired slow speed. Moreover, even after getting into the blood stream, the Naltrexone should metabolize much more slowly than conventional Naltrexone hydrochloride. This produces a dosage vehicle having a long duration bioavailability inside the human body after just a brief inhaling.
Alternatively, in a second embodiment shown in more detail in the Examples below, a therapeutic aerogel powder may be prepared by first forming porous gels from a carrier material which is soluble in pulmonary surfactant, e.g. a sugar or a carbohydrate. This reaction is usually carried out in a solvent. If that solvent will also dissolve the therapeutic agent, then a solution of the therapeutic agent is allowed to penetrate into the pores of the wet gel by soaking until the desired deposition has occurred. If the reaction solvent will not dissolve the therapeutic agent, then the solvent in the resulting gels is first removed by repeatedly exchanging the wet gels with the therapeutic agent solvent (or a close homologue thereof), generally at a temperature between about ambient and 50° C. for a period of about 3–10 hours, and then the therapeutic agent solution is allowed to penetrate the pores. Thereafter the aerogels are formed by supercritical drying at low temperature.
Further alternatively, in a third embodiment when the therapeutic agent is soluble in the reaction solvent, a solution thereof may be added prior to the initial gel formation to avoid the solvent exchange step. Such a process is likely to provide less control of the uniformity of the therapeutic agent deposition and thus is less preferred.
Since the small particle size and high open porosity are critical for fast and even solubility in pulmonary surfactant and absorption at the mucous membrane, the initial aerogel bodies produced by any of the embodiments are comminuted in any suitable manner. Smaller particle diameters can be obtained while maintaining the porous structure by utilizing conventional methods such as impact milling, ball milling, and jet milling. Jet milling in a spiral jet mill has been found capable of producing particles as small as 0.5 micron without lattice destruction or a substantial decrease in open porosity or increase in density. Below a certain size, further reduction may not be warranted since the suspension and dissolving properties of the aerogel particles are so excellent.
The air suspension characteristics of the micron and submicron size aerogel particles are determined using a small chamber with a paddle fan based upon the principle of the lower the minimum air speed necessary to keep the particles afloat substantially indefinitely, the greater the loft and travel of the particles within the air passages of a patient to the lungs. The mechanism of particles floating in the air can be explained as follows: the lift provided by the fluid drag force, that is proportional to the velocity squared, is balancing and overcoming the gravitational pull downward due to density difference between the fluid and the floating particles. The lower the density difference between the floating particle and the fluid, the higher the chances the particle will stay afloat at a given level of fluid motion and the particle dimension. Since the aerogel particles are so porous, up to 95% filled with the same fluid and therefore much lighter than a solid particle, they have much better chances of remaining afloat reaching the innermost part of the lungs and settling on the pulmonary surfactant rather than on the mucous membranes along the way. Since human lungs have an equivalent surface area of a tennis court, it is advisable to take advantage of as much of the surface of the lungs as possible for efficient drug delivery. In actual animal tests, as an animal breathes in air and the air reaches the alveoli, the air velocity begins to slow down and eventually goes to near zero. Therefore, minimum air speed necessary to keep the particles aloft in the particle test chamber is a good measure of how long and how far the particles would stay entrained in the air flow as the air goes through the air pipes and reaches the alveoli of the lungs.
Optionally, additives to reduce static electric charge on the aerogel particles may be used.
The aerogel powders dissolve very fast once exposed to pulmonary surfactant and the water on the mucous membranes. This is due to the aerogel powders having pores that are only a few nanometers in diameter. The capillary pressure is proportional to the surface tension of the fluid and inversely proportional to the characteristic dimension of the pores. The surface tension of water is very high and the same for both a sold particle and aerogel particle. However, the characteristic dimension for a solid particle is the diameter of the particle (e.g., 2.5 micrometer) whereas the characteristic dimension for an aerogel particle is the pore diameter (e.g., 2.5 nanometer). This means the capillary pressure to get the inside pores of an aerogel particle wet could be 1000 times higher than the surface tension force that tends to wet the surface of the solid particles. Combine this with the fact that once the pores of the aerogel particle are filled with the surfactant/water liquid, the dimensions or thickness of the solid material which must be dissolved into the liquid is only 1˜2 nanometers thick, i.e. the aerogel lattice structure forming the pores, as opposed to the one or two micrometer radius of the particle. Thus the speed of dissolution could be 1,000 times faster for aerogel particles as opposed to solid particles.
Another way of looking at the fast dissolution of aerogel particles is based upon the surface area the particle which is exposed to solubilizing liquid. The surface area of a solid ball of 2.5 micrometer is 20×10−12 m2. For aerogel particle of the same diameter with a specific pore surface area of 1000 m2/g and a density of 0.1 g/cc, the interior pore surface area is 8.2×10−10 m2. In other words, the surface area of an aerogel particle is approximately 42 times that of a similarly sized regular solid particles. Since all the pores of the aerogel particle will fill with surfactant/water, the dissolution occurs more rapidly. Therefore, the speed of dissolution of aerogel particles is at least two or three orders of magnitude faster than regular solid particles which means that there is a much faster absorption of the aerogel drug into the blood stream.
Inhalation of certain substances are known to reach the blood stream in 8 seconds: far faster than delivery by intravenous injection. Inhalation delivery via aerogel powder, with its inherently effective reach into alveoli, and extremely quick dissolution and absorption, is an effective, non-invasive and rapid way of administering drugs.
A lot of materials can be produced in aerogel form, including most of the inorganic and organic substances including alkaloids, organic salts, monomers, polymers, proteins, and carbohydrates. This covers a vast variety of medications, both man-made and extracted from natural products. Therefore, the method of aerogel powder inhalation can be utilized as a more effective and non-invasive alternative drug delivery method for treatment of wide variety of diseases and symptoms.
Further examples of aerogel inhalable particles include an inhalable form of insulin and other daily medications that are generally injected with hypodermic needles, such as various vaccines now given by hypodermic or transdermal injections; high blood pressure medications and other pills now taken orally, such as Viagra, that may cause undesirable stomach reactions or are slow to take effect; asthma treating inhalant and cold medicines that would penetrate deeper into the innermost alveoli of the lungs; and other cases where medication is desired to be introduced into the blood stream fast and without invasive or painful measures. In general, the aerogel powder inhalation will be a viable alternative to needle injection, transdermal injections using high speed particle impingement, electric potential, etc., and implantations of slow release capsules.
This drug delivery method produces inhalable forms of common therapeutic drugs such as insulin, aspirin, Viagra®, asthma medications, cold medications, antibiotics, and the like, as long as an aerogelized form of the drug can be produced. Bypassing digestive systems, the medication will take effect much faster and more effectively than is possible today either taken orally, by inhalation or intravenous injection with less trauma and side effects.
A convenient way of using the aerogel powder as inhalants is by means of a portable inhalation device similar to conventional asthma medication devices into which the proper amount of an aerogel powder form of a pharmaceutical will be placed and then shaken or electrostatically dispersed evenly before inhalation.
Another convenient way of using the proposed drug delivery method for treatment of addicts will be placing the subject in a room into which the right concentration of aerogel dust of the selected substance is injected for a required period to reach the target dosage. The size, porosity, and surface area of the particles determine the rate of dissolution of the particles on the surface of the lungs and the rate of diffusion into the blood stream. Once the particle properties are fixed, the rate of the drug delivery can be determined by the concentration of particles in the inhaled air. Other things being equal, the rate of drug delivery will depend on the particulate concentration in the air. The total dosage will depend on the concentration and the exposure duration. The dosage chamber can be designed in such a way that once the desired dosage is reached, before opening the chamber, the particles in the air may be removed by filtering through an aerogel blanket filter. The substances collected by the filter can be recycled.
In those cases where the pharmaceutical aerogel product has to be diluted by means other than airborne dust concentration and/or exposure duration for medical reasons such as toxicity of highly pure substances, a carrier aerogel matrix can be doped with an appropriate level of the pharmaceutical aerogel product. Any such carrier material will have to be completely innocuous and harmless to humans and dissolvable in water also.
Further details and explanation of the present invention may be found in the following specific examples, which describe the manufacture of aerogel products in accordance with the present invention and test results generated therefrom. All parts and percents are by weight unless otherwise specified.
An insulin containing low density aerogel is prepared by first forming an aerogel carrier powder by the transacetalation of a soluble derivatized mannitol compound in a solvent that does not dissolve deprotected mannitol. Deprotection initiates the formation of the gel. These reactions are carried out by combining a diisopropylidene (1,2,5,6-diisopropylidenemannitol) or dibenzylidene (1,3,4,6-dibenzylidenemannitol) derivative of mannitol with an excess amount of a soluble 1,2-diol compound (i.e. (±)−1 phenyl-7,2-ethanediol (PED)), p-toluenesulfonic acid catalyst (0.5–2%), and a non-polar aprotic solvent (toluene or dichloromethane). The solvent in the resulting gels is removed by repeatedly exchanging the wet gels with ethanol at a temperature between ambient and 50° C. for a period of 4–6 hours.
Insulin is penetrated into the pores of the wet gel by soaking the gel with an alcoholic solution of insulin at 37° C. until the desired deposition of insulin is reached.
The alcohol exchanged wet gels are then dried by CO2 extraction at a pressure and temperature above the critical point (about 35° C. and 1250 psi) until all of the alcohol has been removed. The resulting aerogels have a density of 0.02–0.05 g/cm3 depending on the relative amounts of starting sugar derivative and solvents utilized.
The dried aerogels are then milled to a uniform particle size of 2 to 4 microns, by fluid energy milling in a 100 AS Alpine Spiral Jet Mill. Filtered high purity N2 gas (from liquid nitrogen boil-off) is used to drive the milling process and to cool the product and mill surfaces. The cooling is important to minimize destruction of the insulin structure. This milling process gives a high ultra-fine powder portion with sizes between 0.5 to 10 microns. This size range is useful for pulmonary drug delivery. The process is carried out in an inert atmosphere to minimize exposure to potentially active insulin powders.
The pulmonary drug delivery ability of these powders is tested by means of a standardized airway replica system of the nasal, oral, pharyngeal, laryngeal, tracheal, and bronchial regions of the human airways. Repeated deposition and distribution studies under exacting and consistent flow and volume conditions without subject variability are done. Gamma scintigraphy analyses are used to measure total, regional, and local deposition in the replicas. This allows for the precise standardized comparison of formulations and the influences of particle size and inhalation pattern in individuals of different sizes and ages.
The concentration and biological integrity of the insulin is determined by enzyme linked immunosorbant assay, (ELISA), and sodium dodecyl sulfate-polyacrylimide gel electrophoresis, (SDS-PAGE). The ELISA determines the concentration of insulin that has maintained in its active tertiary structure. The SDS-PAGE shows that no breakdown of the insulin occurs during the processing of the aerogel containing insulin.
To determine the biological activity of the insulin in the aerogel preparations, a competitive binding assay is used to quantify the binding and activation of the insulin receptor. Insulin receptor transfected NIH 3T3 fibroblasts are incubated in the presence of the reconstituted powders with varying concentrations of an anti-insulin receptor antibody, which blocks the binding insulin to its receptor. The rate of autophosphorylation of the insulin receptor is measured qualitatively and quantitatively by autoradiography of SDS-PAGE gels, and scintillation counting of the incorporated 32P in each samples.
Speed of dissolution for the insulin containing aerogel powder is measured against that of a regular insulin powder, by having the powder land on simulated mucous membrane and observing the dissolution process under a microscope and also by measuring the pH of the solution immediately behind the membrane. Rate of dissolution in situ is determined by using a hydrogel coated pH electrode that is exposed to insulin aerogel powders. The pH change or glucose/lactose level change in case the glucose/lactose gel is used as a carrier gel as a function of time to give diffusion of insulin to electrode surface. Rate of powder dissolution to form solvated insulin is proportional to the pH change at the electrode surface. The larger, slower to dissolve compounds have a slower pH change.
The aerogel-insulin powder more rapidly dissolves in a more uniform manner than conventional insulin.
The procedure of Example 1 is repeated except the low density aerogel powder containing insulin is formed by the transacetalation of derivatized trehelose compounds instead of the derivatized mannitol compounds. Substantially similar results are obtained.
The procedure of Example 1 is repeated except the low density aerogel powder is made to further contain morphine.
The concentration and biological activity of the morphine in the aerogel preparations is determined by a competitive binding assay that quantitates the binding and activation of the opioid receptor. Cultured neural cells expressing the opioid receptor are incubated in the presence of the reconstituted powders with varying concentrations of an anti-morphine receptor antibody, which blocks the binding morphine to its receptor. The rate of autophosphorylation of the opioid receptor is measured qualitatively and quantitatively by autoradiography of SDS-PAGE gels, and scintillation counting of the incorporated 32P in each sample.
The procedure of Example 3 is repeated except but the low density aerogel powder containing insulin is formed by the transacetalation of derivatized trehelose compounds instead of the derivitized mannitol compounds. Substantially similar results occur.
The procedure of Example 1 is repeated, except the low density aerogel powder is made to contain Viagra™. Viagra™, chemical name 5-[2-ethoxy-5-(4-methyl-piperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, formula C22H30N6O4S, is a potent selective inhibitor of the enzyme phosphodiesterase-5 (PDE-5), which destroys cyclic guanosine monophosphate (cGMP), allowing cyclic GMP to persist, itself a dilator of blood vessels.
In order to determine the biological activity of the Viagra™ in the aerogel powder preparations, a competitive enzyme assay is used to quantitate the inactivation of the phosphodiesterase-5 enzyme. Cytosol homogenates from cells incubated in the presence of 32P-ATP are incubated in the presence of varying concentrations of the reconstituted powders. The rate of cyclic GMP elimination is measured quantitatively scintillation counting of the incorporated 32P in each sample.
The procedure of Example 5 is repeated except that the low density aerogel powder containing Viagra is formed by the transacylation of derivitized trehalose compounds instead of the derivitized mannitol compounds. Substantially similar results occur.
Claims (27)
Priority Applications (2)
|Application Number
|Priority Date
|Filing Date
|US25743600 true
|US10034444 US6994842B2 (en)
|Aerogel powder therapeutic agents
Applications Claiming Priority (2)
|Application Number
|Priority Date
|Filing Date
|US10034444 US6994842B2 (en)
|Aerogel powder therapeutic agents
|US11266805 US20060188451A1 (en)
|Aerogel based pharmaceutical formulations
Publications (2)
|Publication Number
|Publication Date
|US20020094318A1 true US20020094318A1 (en)
|US6994842B2 true US6994842B2 (en)
Family Applications (1)
|Application Number
|Priority Date
|Filing Date
|US10034444 Active US6994842B2 (en)
|Aerogel powder therapeutic agents
Country Status (8)
|US6994842B2 (en)
|EP1343479A2 (en)
|JP2004516304A (en)
|KR20030077544A (en)
|CN1481236A (en)
|CA2429773A1 (en)
|RU2003122515A (en)
|WO2002051389A3 (en)
Cited By (6)
|Publication number
|Priority date
|Publication date
|US20070065373A1 (en) *
|Vectura Ltd.
|Mucoactive agents for treating a pulmonary disease
|EP2130877A1 (en)
|Fibac ApS
|Gel compositions
|US20110056408A1 (en) *
|Aerogel compositions
|US20110086100A1 (en) *
|Attia Yosry A
|Polyethylene Glycol Aerogels for Targeted Delivery of Pharmaceutical Drubs
|US9757529B2 (en)
|Otitopic Inc.
|Dry powder inhaler and methods of use
|US9757395B2 (en)
|Otitopic Inc.
|Dry powder inhaler and methods of use
Families Citing this family (11)
|Publication number
|Priority date
|Publication date
|DE10214226B4 (en) *
|Arlt, Wolfgang
|Drug carrier, a process for its preparation and use
|US20040121003A1 (en) *
|Acusphere, Inc.
|Methods for making pharmaceutical formulations comprising deagglomerated microparticles
|US6931888B2 (en) *
|Ferro Corporation
|Lyophilization method and apparatus for producing particles
|US20040180915A1 (en) *
|Xanodyne Pharmacal, Inc.
|Methadone-containing compositions for parenteral administration and method of use thereof
|KR100963914B1 (en) *
|유로-셀띠끄 소시에떼 아노님
|Tamper resistant dosage form comprising an adsorbent and an adverse agent
|WO2006016981A3 (en) *
|Ferro Corp
|Production of porous materials by supercritical fluid processing
|US20060127442A1 (en) *
|Helmus Michael N
|Use of supercritical fluids to incorporate biologically active agents into nanoporous medical articles
|EP2389159A1 (en) *
|Noramco, Inc.
|Process for preparing particles of opioids and compositions produced thereby
|JP5883687B2 (en) *
|Pde5 inhibitor-containing pharmaceutical compositions
|CN102961342B (en) *
|Nanoscale capecitabine and preparation method thereof
|US20160058045A1 (en) *
|Pepsico, Inc.
|Method of Loading Flavor into an Aerogel and Flavor Impregnated Aerogel Based on Food Grade Materials
Citations (7)
|Publication number
|Priority date
|Publication date
|WO1995001165A1 (en)
|Holmes, Michael, John
|Medical use of organic aerogels and biodegradable organic aerogels
|US5864923A (en) *
|Cf Technologies, Inc.
|Method of forming particles using a supercritical fluid
|US5958589A (en)
|The United States Of America As Represented By The Secretary Of Agriculture
|Starch-based microcellular foams
|US5981474A (en) *
|University Technology Corporation
|Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
|US6123936A (en) *
|Inhale Therapeutics Systems, Inc.
|Methods and compositions for the dry powder formulation of interferons
|US6277489B1 (en) *
|The Regents Of The University Of California
|Support for high performance affinity chromatography and other uses
|US6403056B1 (en) *
|Imarx Therapeutics, Inc.
|Method for delivering bioactive agents using cochleates
Family Cites Families (1)
|Publication number
|Priority date
|Publication date
|DE19506141A1 (en) *
|Hoechst Ag
|Use of aerogels in the pharmaceutical, cosmetics and phytosanitary
Patent Citations (7)
|Publication number
|Priority date
|Publication date
|US5981474A (en) *
|University Technology Corporation
|Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
|WO1995001165A1 (en)
|Holmes, Michael, John
|Medical use of organic aerogels and biodegradable organic aerogels
|US5864923A (en) *
|Cf Technologies, Inc.
|Method of forming particles using a supercritical fluid
|US6123936A (en) *
|Inhale Therapeutics Systems, Inc.
|Methods and compositions for the dry powder formulation of interferons
|US5958589A (en)
|The United States Of America As Represented By The Secretary Of Agriculture
|Starch-based microcellular foams
|US6403056B1 (en) *
|Imarx Therapeutics, Inc.
|Method for delivering bioactive agents using cochleates
|US6277489B1 (en) *
|The Regents Of The University Of California
|Support for high performance affinity chromatography and other uses
Cited By (10)
|Publication number
|Priority date
|Publication date
|US20070065373A1 (en) *
|Vectura Ltd.
|Mucoactive agents for treating a pulmonary disease
|US7928089B2 (en)
|Vectura Limited
|Mucoactive agents for treating a pulmonary disease
|US20110217339A1 (en) *
|Vectura Limited
|Mucoactive agents for treating a pulmonary disease
|US20110056408A1 (en) *
|Aerogel compositions
|US9827296B2 (en)
|Encoat Aps
|Aerogel compositions
|EP2130877A1 (en)
|Fibac ApS
|Gel compositions
|US9125872B2 (en) *
|Yosry A. Attia
|Polyethylene glycol aerogels for targeted delivery of pharmaceutical drubs
|US20110086100A1 (en) *
|Attia Yosry A
|Polyethylene Glycol Aerogels for Targeted Delivery of Pharmaceutical Drubs
|US9757529B2 (en)
|Otitopic Inc.
|Dry powder inhaler and methods of use
|US9757395B2 (en)
|Otitopic Inc.
|Dry powder inhaler and methods of use
Also Published As
|Publication number
|Publication date
|CN1481236A (en)
|JP2004516304A (en)
|WO2002051389A3 (en)
|EP1343479A2 (en)
|US20020094318A1 (en)
|KR20030077544A (en)
|WO2002051389A2 (en)
|RU2003122515A (en)
|CA2429773A1 (en)
Similar Documents
|Publication Date
|Patton et al.
|Inhaling medicines: delivering drugs to the body through the lungs
|US7625865B2 (en)
|Insulin highly respirable microparticles
|Ungaro et al.
|Insulin-loaded PLGA/cyclodextrin large porous particles with improved aerosolization properties: in vivo deposition and hypoglycaemic activity after delivery to rat lungs
|Lüllmann et al.
|Color atlas of pharmacology
|Dellamary et al.
|Hollow porous particles in metered dose inhalers
|Newman et al.
|Evolution of dry powder inhaler design, formulation, and performance
|US8278308B2 (en)
|Diketopiperazine salts for drug delivery and related methods
|US20040204440A1 (en)
|Composition, device, and method for treating sexual dysfunction via inhalation
|US20070261695A1 (en)
|Sublingual fentanyl spray
|US20030175214A1 (en)
|Formulations for use in inhaler devices
|US20020052310A1 (en)
|Particles for inhalation having sustained release properties
|US20030232019A1 (en)
|Inhalable formulations for sustained release
|EP2050437A1 (en)
|Improved pharmaceutical dry powder compositions for inhalation.
|US7048908B2 (en)
|Particles for inhalation having sustained release properties
|US6586008B1 (en)
|Use of simple amino acids to form porous particles during spray drying
|Shoyele et al.
|Prospects of formulating proteins/peptides as aerosols for pulmonary drug delivery
|US6153224A (en)
|Carrier particles for use in dry powder inhalers
|WO1995024183A1 (en)
|Methods and compositions for pulmonary delivery of insulin
|US20040042970A1 (en)
|Inhalable sustained therapeutic formulations
|WO2001013892A2 (en)
|Large porous particles by spray-drying
|US7879358B2 (en)
|Pulmonary delivery for levodopa
|WO2001085137A2 (en)
|Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
|US20070031490A1 (en)
|Effervescent powders for inhalation
|US7052678B2 (en)
|Particles for inhalation having sustained release properties
|US6193954B1 (en)
|Formulations for pulmonary delivery of dopamine agonists
Legal Events
Owner name: ASPEN AEROGELS,INC., MASSACHUSETTS
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LEE, KANG;GOULD, GEORGE;REEL/FRAME:012674/0897
Effective date: 20020221
Owner name: ASPEN AEROGELS, INC., MASSACHUSETTS
Free format text: MERGER;ASSIGNOR:ASPEN AEROGELS, INC.;REEL/FRAME:021194/0248
Effective date: 20080610
Owner name: ASPEN AEROGELS, INC.,MASSACHUSETTS
Free format text: MERGER;ASSIGNOR:ASPEN AEROGELS, INC.;REEL/FRAME:021194/0248
Effective date: 20080610
|Maintenance fee reminder mailed
|Surcharge for late payment
|Fee payment
Year of fee payment: 4
Owner name: SILICON VALLEY BANK, CALIFORNIA
Free format text: SECURITY AGREEMENT;ASSIGNOR:ASPEN AEROGELS, INC.;REEL/FRAME:030157/0815
Effective date: 20130328
Owner name: PJC CAPITAL LLC, MINNESOTA
Free format text: INTELLECTUAL PROPERTY SECURITY AGREEMENT;ASSIGNOR:ASPEN AEROGELS, INC.;REEL/FRAME:030292/0456
Effective date: 20130404
|Maintenance fee reminder mailed
|Surcharge for late payment
Year of fee payment: 7
|Fee payment
Year of fee payment: 8
Owner name: ASPEN AEROGELS, INC., MASSACHUSETTS
Free format text: TERMINATION AND RELEASE OF INTELLECTUAL PROPERTY SECURITY AGREEMENT;ASSIGNOR:PJC CAPITAL LLC;REEL/FRAME:033253/0985
Effective date: 20140626
Owner name: ASPEN AEROGELS, INC., MASSACHUSETTS
Free format text: RELEASE OF SECURITY INTERESTS;ASSIGNOR:SILICON VALLEY BANK;REEL/FRAME:033686/0702
Effective date: 20140903
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.)


text:
Kentucky football says they're a much different team than the one that fizzled out last season
There's no question that the expectations for Kentucky football in the third year under Mark Stoops is expected to be a far more impressive product than what it was when he arrived. It's a team that is faster, stronger and more built for the tough grind of an SEC schedule than it's been for quite some time.
During the team's appearances at SEC Media Days, the players said they're not dwelling on last season and they feel like a completely different team.
Below the Fold
Subscribe and get the latest KSTV Sports info delivered to your inbox.

subset: commoncrawl


text:
All Games
My Giosti
Create an account
Halloween Games
Cartoon Network Games
Adventure games
Barbie games
Action games
Casino games
Decor games
Funny games
Handling games
Logic games
Makeover games
Matching games
Spring Games
Car Games
Sport games
Animal games
DJ Alien: Let the Music Play
Giosti - Games for girls and for boys - Games for children
Please like us on Facebook
DJ Alien: Let the Music Play is a funny game that is aimed at children aged 5 to 10 years.
Drink DJIti like music? We have a proposal for you. How about you be our DJ today? :) Show us how good you are in the field! Use you mouse to mixezi music:)
DJ Alien: Let the Music Play
Play it later
Rate this game:
Funny games
Music Games
Glops: Balls with Attitude
Click on Glops of the same color that are grouped together to remove them.
SpongeBob Squarepants: Atlantis Squarepantis: Bus Rush
SpongeBob: Atlantis Squarepantis: travel by bus is a fun game that tests your...
United We Dance: George Bush and Britney Spears
You control Britney & Bush as they hit the dance floor!
Frisbee Dog: Sheep Pool
Order oiteleObiectivul game is very simple ... Use Frisbee dog to numbered...
Shrek the third: Shrek 'n' Slide
This is a funny game with the big Shreck. Hit the spacebar as close to the end...
Shrek and Fiona: The Battle of the Belch
This is a game with the funny cartoon characters Shrek and Fiona. The two are...
George of the Jungle: Swinging Kingdom
Swinging Kingdom
Crazy nut: Up in the Ski
Get up to see where you can get? Use the SPACE key to bounce and LEFT-RIGHT...
Whee eee!
Cheese goes with wagon - As you probably know, Cheese is a new member of the...
Totally Spies: Dance
Let's dance with Spies. Instructions: There are two series of dance steps....
My "Dear" Boss
Show them who's boss.
Mid Flight Snack: Get the Candies
Blue, Mac si Eduardo! Fun with them!
Headless Robot Joe
Lucky for Joe, there's still hope for robots without heads!
Foster's Home: Team Work
Use oula Coco's to catch the bombs before they explode.
Morning aerobics
Moves out along with other athletes. If you really want to be part of the band...
Hacker: Break the Computer
Hack the Planet!
Warren: the Party rabbit
Welcome to the Zoo bar, the hippest, hottest spot in town. Our hero, Warren,...
Blobz: Watch Him Explode
Play against the PC or friend to try to explode your cute little blobz before...
You Don't Mess with the Zohan
Stylist Zohan went to dress people who jumped out of the way they look. So ...
Honey Bunny: Hunt for Honey
Bunny in the game you must collect all the jars of honey and to go home, watch...
Flying Gonzo
Fire gonzo away right into the bucket of stunt water!
Krave: Hang in the Wire
This is an interesting game where the goal is to rotate the mobile object so...
Blair The Motivator: Morning Workout
Can you help Tony motivated the party into shape?
Destroy the computer
It is impossible not to be never had problems with your computer. When you give...
Robot vs. Zombies
It's time for the undead to meet their match: robots!
Music game
Typing game
Float: Collect the Stars
Keep your ball alive without hitting the spikes and gather as many stars as...
Squirrel Cannon
It's raining squirrels!
SQRL Golf - 2
This is the sequel to the popular golf game Squirrel
Dancing Tony Blair
Watch Blair Dance!
Be an artist!
Be an artist! An Indian beat on drums, compose your own song. Use you mouse.
Pp man: Save Spain
You are in beautiful Spain. But there is a problem. The country is in chaos....
Dancing Queen
You're dancing like a little practice for the big show. You have to move fast...
Roof Top Rollers
Click on the instrucments to make those cats swine
Mechanic Pig
This little piggy went to market, this little piggy…flew to paradise?
Blobo: Get Out of the Box
Help Blobo collect all the candy and beware purple monsters!
Dancing Ant
Configure and direct how the any should react to the music
Peanut: Hit the Peanut
You play the part of a bored guy waiting in the bar for your mates. Just as you...
Jump 'n' Bump
You're a funny ball which is crazy for stars, but you must be careful as some...
Sheeps: Dreaming of Sheeps
Help the sheep jump all the obstacles!
Bush Aerobics
Help President Bush get fit and ready for the sweetest day of his life .
Clowns: Circus is in the Town
Your job is to impress the crowd as much as your can with your clown skills and...
The Jumping Troll: Magic Mushroom
Help the little control to jump on the mushroom, collect all the fruit and make...
Highway To Bunny Heaven
Objective: Look out for cars in traffic and collect eggs that have the same...
Amigo Pancho 2: New York Party
Fly high with Amigo and his balloon-powered dreams!
Blob Farm
Keep the blobs safe. Drag and drop them out of Harms away. Keep them away from...
Cats Cannon
These fearless felines are ready to fly!
RayRay: Ray and his Friends
Try to get all of the RayRay to stand.
Cherie 'Disco' Blair
Check out Cheries moves!
View the dance move pattern, use the Num keys, hit Space and break dance!
giosti.com :: 2009 - 2018 :: Games for girls and for boys - Games for children - Giosti . All games rights belongs to the games developers.


text:
"A new baby is like the beginning of all things-wonder, hope, a dream of possibilities."
~ Eda J. Le Shan
image via mikefiectnerphotography
You are too cute! You look fantastic! Can't wait to "meet" your little one via blogland!
Aww, you're looking lovely!
You look gorgeous, almost there!
Love this picture so much!


text:
Governor Ernie Fletcher's Communication Office
Governor Ernie Fletcher names Edwin Orange Assistant to Governor for Boards and Commissions
FRANKFORT, Ky. - Governor Ernie Fletcher announced today the appointment of Edwin Orange as the administration's new assistant to the Governor for Boards and Commissions. Orange most recently served as deputy director of Boards and Commissions during the first 20 months of Governor Fletcher's administration.
"During his time working in Boards and Commissions Edwin has proven to be effective and knowledgeable," Governor Ernie Fletcher said. "The management of our Commonwealth's boards and commissions is an important component to ensuring economic and educational opportunities for every Kentuckian."
Orange is a native of Logan County and received his bachelor's degree from the University of Kentucky. Orange currently serves as the second vice chairman of the Friends of Kentucky 4-H. He is the son of Charles and Jo Orange of Russellville.
"I am honored that Governor Fletcher has placed this trust in me," Orange said. "Citizen involvement in government is important. I am committed to ensuring that all of Kentucky is represented on these boards and commissions."
Orange replaces Teresa Hill, who has been named commissioner to the Public Service Commission.


text:
HPD Latest News
UPDATE: Man wanted for assault arrested
The man featured on a CrimeStoppers bulletin for assault has been arrested. HPD officers arrested Rudy McMahan Wednesday in Waianae thanks to an anonymous tip.
CrimeStoppers and the Honolulu Police Department need the public's help locating Rudy McMahan, who is wanted for two $11,000 Probation Revocation warrants for failure to comply with terms and conditions of probation.
On March 3, 2013, McMahan assaulted a female and fled the scene in her vehicle. March 28, 2013, McMahan assaulted another female and fled the scene prior to police arrival. On April 21, 2013, McMahan assaulted the same victim from the March 3, 2013, incident and fled prior to police arrival. McMahan is wanted for two counts of Assault in the second degree, two counts of Abuse of a Household or Family Member, Terroristic Threatening in the second degree, and Unlawful Imprisonment in the Second Degree.
Rudy McMahan is 38-years-old. He's 6'2" tall, weighs 185 pounds and has numerous tattoos on his body, including the words "player" on his neck area.
Anyone with information about this incident is asked to call CrimeStoppers at 955-8300, or *CRIME on your cellular phone. Free cellular calls are provided by
AT&T, Nextel Hawaii, T-Mobile, Verizon Wireless Hawaii, Mobi PCS, and Hawaiian Telcom. The public may now send anonymous text and web tips. Text "CS808" plus your message to 274637 or CRIMES.


text:
We talk to people working in and around the profession, to glean how far diversity efforts have come and where they are headed in the future...
THERE'S a clear consensus that diversity in the legal profession matters, but what exactly do we mean by the term? Charlotte Wager, partner at Jenner & Block, ruminates: "There are lots of different levels of diversity. It's not a static concept – it changes over time." At the moment, NALP collects statistical information in order to track the spread of women, ethnic minorities and LGBT individuals, but what about the much broader categories? How else can we categorize diversity? In terms of age, disability, religion, socio-economic status? The very act of trying to define diversity is part of the problem, and one that perhaps makes firms recoil from the quandary of who is considered, and whether to assign priority to certain groups over others.
It's not just a semantic quandary, but a practical one too, as Lori Lorenzo, deputy director of the Leadership Council on Legal Diversity, states: "The problem is broad and includes issues related to pre-law advising, law school admissions, law school success, Bar passage, hiring, promotion and retention, just to name a few."
Given the enormity of the task, it's easy to see how so-called 'diversity fatigue' has set in among many in the industry. During NALP's 2013 conference, a range of speakers presented on the extent to which students and lawyers had become skeptical and weary of diversity initiatives and their impact. Some blame the global recession: while the intention to create diverse workforces is still there, the resources are not. Others report that students are becoming more skeptical, and posing increasingly probing questions to recruiting panels at OCIs: 'Yes, you've got all of these initiatives, but what do you actually do? Are you just ticking boxes? Are you really serious about these commitments or is it just window dressing?'
Long is the way
"Nobody can say that it has been a smashing success. Just look at the numbers – they are often depressing, and private law firms continue to struggle," comments Joshua Wayser, managing partner at Katten Muchin's Los Angeles office and cochair of the firm's LGBT coalition.
According to the latest data published by NALP in December 2013, only very small gains have been registered since 2009. Female partners made up 19.21% of the partnership in 2009, while in 2013 the figure increased to just 20.22%. The data for minority partners reflects a similarly scant increase, from 6.05% to 7.10%. Worryingly, the percentage of women associates has dipped, from 45.66% to 44.79%. Jim Leipold, NALP's executive director, had this to say on the findings: "While the percentage of women partners, small as it is, has continued to grow each year, sustained incremental growth in the future is at risk if the percentage of women associates continues to inch downwards. This should be a red flag for everyone in legal education and the law firm world."
NALP stats in recent years also suggest that women and minorities have had more success elsewhere, pursuing other options (such as clerkships, public interest work or academic positions) which perhaps put up less resistance than the path into BigLaw.
However, the term 'inclusion' is becoming something of a buzzword. Jason Gibson, a former president of The National LGBT Bar Association, tells us: "The idea of inclusion goes beyond the principle of 'I have to have you on my team because you're African American.' It's a broader conversation about how everyone can participate, and how teams can work better together – it's about wanting everyone to be at their best. As a function of that you create a diverse environment." Placing diversity within this much broader, more cohesive framework may help to tackle the issue at its very center.
Overcoming bias
In order to understand how the profession can improve in its stride for inclusiveness, the idea of implicit (or unconscious) bias has to come into play. Much of the conversation surrounding this idea has been stimulated by UCLA Law Professor Jerry Kang, who has given a series of presentations on the presence and impact of implicit bias in law. Kang's research adds to a wide range of studies that reflect implicit bias, and Wayser describes one which demonstrated how "babies crawl away from the people that they look different from and crawl towards the people that look like them." The conclusion is that implicit bias is so innate, so ingrained within our earliest nature, that we carry it with us and exercise its effects in the workplace. We don't necessarily recognize when we're favoring our own and excluding others.
Wayser identifies why implicit bias is such a problem in the legal profession: "Law is about trust – the trust that has to be built with your clients and colleagues in order to succeed." We find ourselves being "implicitly biased despite our best intentions," Wayser explains. "There seems to be a built-in and unrecognized hesitancy to trust people who are different to you. It can put minorities at a disadvantage."
How can we make people consciously aware of unconscious bias? "Obviously we can't over-engineer everything," says Kristine McKinney, director of diversity and inclusion at Faegre Baker Daniels, "but there are simple things that we can do, and we often forget to do them." These might include introducing techniques which allow everyone to speak during meetings; these techniques are especially relevant in an age of routine teleconferencing, in which people can quite easily be sidelined.
The process goes deeper than that though, and requires law firms to reconsider some of their most fundamental structures, and re-examine policies surrounding elements like compensation, origination credit and succession planning. Let's take a look at a common example: the use of a free market system. To many firms, the free market system makes business sense: young attorneys learn who they like working with and work with the same people habitually; the clients like the sense of continuity that comes from dealing with the same people; and a team is subsequently formed that is well educated about the client. From a business perspective, it's a win-win situation. Charlotte Wager explains that "it can have a negative impact, too. Sometimes a free market system means that people end up forming smaller, informal groups often around particular clients or partners with business. If you are in such a group you reap the benefits. But for women and people of color, it can be hard to get in the group and then it might be harder to get access to quality work opportunities or enough work."
Consequently, law firms are starting to think of ways to tweak their free market systems in order to broaden access to key teams, clients and cases. It's not necessarily that the system itself is bad, just that it needs some fine tuning. As McKinney states, "a lot of the time firms will put a lot of work and energy into recruiting minority attorneys, but then they will unintentionally put them into offices out of the way. You have to think about the way in which work patterns occur." This is why seemingly minor factors like a person's location in the office can have an enormous impact, and all it requires is that law firms pay closer attention to the areas of an office which are particularly active or ripe with opportunities, and then place someone who could potentially be marginalized closer to them.
Mentorship programs
Informal mentorship programs are another staple of law firm life, and form the backbone of many diversity initiatives. Do they work, though? Such mentorships do of course have their value, but there's a sense that a more formalized and robust relationship is needed. Wager tells us: "We know from research by the American Bar Association and others that the presence of a mentor has a huge impact on how women, particularly women of color, experience life in a large law firm. If a formal mentoring program exists, you can pair people across diversity and ensure that women, people of color and other underrepresented groups have access to mentors who are plugged in and good sources of work and information. In an informal mentoring system, where associates and partners select their own mentors, this might not happen. People have a tendency to gravitate toward people who they perceive as similar and this often means people who look alike. So straight, white men end up mentoring straight, white men. Some of that is obviously fine, but we all benefit when we have mentoring relationships that build relationships across differences including race, gender, sexual orientation. Especially those who are traditionally underrepresented in large firms."
Paulette Brown, partner and chief diversity officer at Edwards Wildman, raises a key point: "If there is a formal mentoring program, arbitrary assignments should not be made. Mentors should volunteer to ensure a more effective mentoring program."
For many, the logical conclusion of constructing a more formal program goes beyond just mentorship, and takes on the form of sponsorship. Such programs are becoming increasingly popular, and are designed to pair a mentee with someone who will actively advocate for their advancement. Jason Gibson says: "People are always willing to share their ideas, but what you need is someone who is willing to speak on your behalf. You can have all the talent in the world, but if no-one knows that, what use is it? You need someone to take a stake in your name and your work product, to vouch for you when you are not in the room, and to use their relationships and influence to create opportunities for you."
Becoming one of them
Sometimes removing unintentional bias can come down to scrutinizing the language we use. Lori Lorenzo, who has delivered presentations on language training, tells us that just changing a word can help to foster a more inclusive environment. For example, using the word 'partner' (instead of 'husband' or 'wife') during a conversation can make it easier for LGBT individuals to feel included. Often people are afraid to initiate a conversation in case they use the 'incorrect' word and unintentionally create the impression of bias, but, as Lorenzo states, "it's okay to say it wrong or to use the wrong word, just correct yourself." The fact that a conversation or a dialogue has been initiated is what's important.
Minorities also have to consider what they can do to minimize the barriers. "For me, it's important to work at a firm where I can maintain my identity," says Gibson, "but on some level you have to be willing to 'play the game' and fit into the culture of the firm." Joshua Wayser adds: "You have to show that you are a lawyer that your clients can trust and see commonalities with. You have to reach out to people in order to build bridges, so that you're not the 'different person'. It's like brand management. At the end of the day law firms are still largely controlled by those who are not minorities, so it comes down to how well you can deal with them, how much you know about how the system works and how the business world works. You've got to know the rules of engagement." Formal and informal mentorships may help to get that process under way, but nonetheless an effort has to be made on the minority's part as well.
This doesn't mean that a minority attorney should hide aspects of themselves – like their sexuality – or downplay elements that are crucial to their sense of self and identity. As Wayser says, "you have to be yourself; you can't hide because then people will also experience discomfort." What it does mean is that minorities have to strike a balancing act between preserving the things that constitute their identity while at the same time reaching out, displaying the intuition and shrewdness required to tease out the commonalities they share with people from whom they are ostensibly different.
There's only so far a person can go to fit into a firm's culture; it's crucial that minorities do their research on firms before settling on one for their career. For example, an LGBT law student would do well to scrutinize a firm's policies and statistics (Do they offer domestic partner benefits or the gay gross-up?1 How well do they score on the HRC index for LGBT equality?). These are all indicators, but some firms will be supportive despite a below-average performance in the stats.
Some firms are adopting policies to help make particular life choices (like raising children) viable and sustainable. For example, some firms are now installing a new billing levels model, which, as McKinney describes, "provides more flexibility, so that instead of having class years, people can pace themselves and say 'I'm a dad and I want to stay at this billing rate and salary for the time being'." It's also important to try to ascertain how much policies are actually utilized by attorneys. This is especially relevant when it comes to flex-time and maternity/paternity policies: the firm may offer 16 weeks of paid maternity leave, but how many women take the firm up on the offer and make it culturally acceptable?
Pipeline projects
When it comes to creating a profession that is more ethnically inclusive, the challenges become far more complex, and can't just be addressed by a firm internally, but instead require far grander efforts to improve the demographics. This is hardly the platform for such a huge topic. However, one current project addressing this is all about pipeline programs into the legal profession. Their goal is to help minorities from underserved communities establish a continuous path: one which will get them through high school, college, law school and, finally, into a law firm. James O'Neal has established an organization, Legal Outreach, which aims to do just that.
It is right, then, that the drive should now be to address the root causes, rather than simply assuaging some of the symptoms. Developing such change relies on, as Charlotte Wager says, "open dialogue and discussion within firms so they can examine their own cultures and any unconscious bias that may exist. When it comes to tools and strategies for changing the status quo, there is no one-size-fits-all." It doesn't necessarily matter if one idea isn't that successful, as Lori Lorenzo highlights: "It's about taking action, measuring results, and not being afraid to make a course correction when necessary."
While the current NALP statistics don't exactly give cause for unbridled joy, the move toward a more cohesive and less problematic framework under the banner of inclusiveness, combined with a more informed grounding in sociological habits, has propelled people to get increasingly practical and inventive, indicating that a more inclusive industry may be on the horizon.
Want to be a BigLaw parent? Find out which firms will help you>>


text:
TOY STORIES: ITC exhibit spans 300 years of Texas playthings
Updated 8:34 am, Monday, November 28, 2011
The doll in Sarah Gould's hands tells a story.
At first it's Little Red Riding Hood, ready for that sojourn to Grandma's house. Then with a half-spin and a full flip of its long skirt, it turns into Red's grandmother. A tug on Grandma's nightcap then swallows her smile to reveal the fiendish face of the Big Bad Wolf.
Such topsy-turvy dolls date back to before the Civil War, when a white doll on one end usually hid a black doll on the other and vice versa. But for Gould there's yet another tale behind her storybook doll.
"My grandmother made this for me," she says.
Gould's doll is just one of many storied playthings on display at "Timeless Texas Toys," a new exhibit at the Institute of Texan Cultures. The walk-in toy box remains open through Aug. 5, 2012.
"Timeless Texas Toys" showcases handmade and manufactured toys of yesteryear. Most come from the early- to mid-20th century, though among the china dolls and toy cars you'll also find stone game discs from Mission Espada that predate its 1690 founding and a paper doll illustration of that 21st-century sensation Beyoncé.
Entertainment Channel
- 'Dynasty' actress: Remake series 'a rollercoaster ride' Associated Press
- 5 Facts About Dennis Quaid, From Us Weekly Wibbitz
- Kendall Jenner Finally Addressed The Rumors About Her Sexuality MarieClaire
- Rambin: I was 'an awful judge of character' Associated Press
- Spielberg: 'Black Panther' will 'really change things' Associated Press
- Perrie Edwards RESPONDS To Gigi Zayn breakup, Cardi B's Baby Due Date! | MOTW Hollyscoop
- Bella Thorne Dating HOW MANY People?! Hollyscoop
- Britt Robertson's harsh words for Arie Luyendyk Jr. Associated Press
- Camila Cabello FINALLY Opens Up About Matthew Hussey: Addresses Taylor Swift Rumors Hollyscoop
- Mean Tweets: Khloe Kardashian Receives A TON Of Hateful Messages For Maternity Photo Hollyscoop
Children who visit the exhibit can also make-and-take their own folk toys, some themed to San Antonio events like Chinese kites for the Asian Festival and corn husk dolls for Fiesta. The exhibit doubles as a toy workshop with tables and workbenches among giant Styrofoam letter blocks and jumbo replica toys like a big wooden climbing bear and cascading Jacob's ladder.
The goal of the exhibit: Connect kids of all ages with toys across the ages, and uncover some very real stories behind these very memorable avenues of make-believe.
"Historically, a lot of toys have been about training children for what their future is going to be," says Gould, ITC researcher and curator for the exhibit.
For the longest time that meant housework toys for girls and hunting toys for boys, usually from the local toy maker. Gould says that changed after the Civil War with the emergence of the American toy industry. The railroad and industrialization for mass manufacturing helped, she says, along with more discretionary income for parents.
Yet at the heart of the modern toy era was a new perspective parents had for their children, which Gould says stemmed from a need to rejoin post-Civil War families and cultivate a child's formative years. Parents now saw childhood as a separate stage of development, one that should be preserved as well as celebrated. Simply put, kids deserved to be kids.
"And so toys really came to be understood as children's tools," Gould says. "Play is their work, and toys are their tools."
The ITC exhibit highlights plenty of tales behind those tools.
Consider the story of Margaret Brack, who ran what Gould believes was one of the state's first doll hospitals right here in San Antonio.
Brack inherited the Original Doll Hospital from her mother, Mellie Pegg, who Gould figures opened the hospital in 1916. There, doll owners could replace or repair a broken arm or leg of their fragile composition and bisque porcelain playmates. Brack ran the doll hospital until her death in 1956.
The Timeless exhibit will showcase various doll parts that represent those repairs, along with a photo of Brack in her workshop.
Then there's the heartwarming story of German furniture and toy maker Louis Dietz in Seguin and the little Orphan Train girl who inspired his most unifying creation.
In 1910, Dietz and his sister took young Alice O'Brien into their home. Besides Dietz's home to call her own, Alice would also have her own child-sized Victorian doll house Dietz built for her. The ITC exhibit will show a doll vanity from the doll house, along with a giant photo of the dandy dwelling.
In 1967, the property's owner, Pablo Castilla, and his son Ralph gave the doll house to the Seguin Conservation Society. Today, the repaired and rechristened Dietz-Castilla Doll House serves as testament to not only Dietz's love for his child but also a community's love for its history and multiculturalism.
"This little doll house to me is just a jewel in the crown that is Seguin, Texas," says Bobbie Maddox, conservator of the doll house along with her husband, Marvel.
Of course the ITC exhibit also remembers the Alamo with toys such as a Davy Crockett coonskin cap from the 1950s and a Davy Crockett at the Alamo toy playset. As Gould says, "Texas history entered the toy box, in a sense, through Disney."
For some real playful pop culture history at the exhibit, patrons can enjoy a sampling of the whimsical paper dolls by Tom Tierney.
Originally a fashion illustrator, the 83-year-old Tierney has drawn paper dolls over the decades for just about every (undressed) celeb from as far back as Clark Gable to as recently as Edward the vampire from the "Twilight" movies.
For the ITC exhibit, Tierney provided original art from his two Texas paper doll books, "Famous Texas Women" and "Famous Texas Men." Expect several famous Texans in 2-D skivvies, such as former Texas Gov. Ann Richards in garter stockings and country crooner George Strait in tighty-whiteys.
"It's amazing how many talented people come out of Texas," says Tierney, a Beaumont native who lives in Smithville.
And amazing how such toys of old remain beloved in an age of interactive dolls and motion-controlled video games. Gould is working on a book manuscript based on her dissertation, which chronicles the history of ethnic imagery in American toys and how that industry continues to talk to kids about race and American identity.
Like her grandmother's doll, another playful story to pass along.
"I have a particular love for toys as a subject which offers, I think, a fantastic window not only into history but also who we are as a culture," Gould says.


text:
Review by chopsof1980
October, 03 2008
Pros: The T.V. works alright.
the dvd player sucks.
Review by michellgomez
December, 23 2007
Pros: Price.
Cons: Everything else.
Review by consumerno13
December, 31 2006
Pros: Flat top, inexpensive, good quality sound and picture.
Cons: It's pretty large... not great for a dresser or transferring in small vehicle.
Review by Ginger_1
August, 20 2006
Pros: Convenience of a combo, makes a nice bedroom t.v. with the sleep timer
Cons: DVD player tends to have technical issues.
Review by _serenity_
July, 28 2006
Pros: NONE right now... I'm P*SSED
Cons: DVD PLAYER WON'T OPEN. Opened it only an hour ago ... and NOTHING
Review by nomorerca
January, 02 2006
Pros: Makes a dang nice door stop, paper weight or step stool.
Cons: RCA customer service and website are a joke.
Review by okdeb
October, 26 2005
Pros: None - never worked at all out of box
Cons: Never worked, Not much help from manufacturer
Review by bmowrer
July, 28 2005
Pros: TV/DVD/CD/MP3 Combo - great for my budget and purpose.
Cons: Is a bit large for on the dresser - but I will live with that.
Review by swamppup
May, 10 2005
Pros: There is only one pro about this unit. The TRU Flat screen
Cons: THE REST OF THE UNIT
Review by jeof0411
January, 30 2005
Pros: Multiple Uses, Flat Tube, Great price, Front rear A/V, S video
Cons: Flat tube doesn't offer as much difference as HDTV.


text:
SRINAGAR, INDIA — Avalanches and extreme cold have killed at least 284 people in the divided Himalayan province of Kashmir, and about 150 others are missing on both sides, Indian and Pakistani officials said Tuesday.
Heavy snow has gripped the region since last week, temperatures have dropped to minus 34 and rescue workers are finding more bodies beneath the snow. Avalanches have closed roads throughout the region, cutting off Indian and Pakistani residents for the fifth straight day. Indians in one region were ordered to evacuate immediately.


text:
Although Michigan's firearm deer season is just a little over a week away, hunters limited to shotguns in the more densely populated southern tier of the state still have time to make sure their firearms can place a slug where the shooter wants it to go.
But according to leading experts on shooting slugs, sighting in many shotguns to shoot accurately is slightly more involved than sighting in a rifle.
That's especially true of the popular pump-action shotguns that many hunters use. Pump guns are top choices among Michigan hunters, who use them for upland game with a longer, smoothbore barrel, then switch to a rifled barrel for the firearm deer season.
"Hunters who switch out barrels really should sight-in the shotgun every time the rifled barrel gets reinstalled," says John Clark, a veteran slug shooter and firearms instructor who does most of his deer hunting in the Battle Creek area of southern Michigan. "Plus, if a hunter is serious about taking a deer, sighting the shotgun is a good time to practice for shooting accurately when a deer comes into shooting range. Hunters should be confident in their ability to hit what they're aiming at and there's no substitute for going to a range or setting up a range and popping some caps at a target."
Clark says that pumps need special attention because of the inherent looseness of the forend that the hunter "pumps" to eject shells.
"The forend on the shotgun has some side-to-side play that can cause a slug to go off target," says Clark. "The most important thing when it comes to consistent accuracy is to be aware of that play—and to get rid of it."
Accomplishing that goes against what many shooters are initially taught about firing long guns.
"Just about all of us were taught to relax and not grip the forend too tightly when we learned how to shoot rifles," Clark says. "With a pump shotgun, you not only have to grip the forend fairly tightly, but you also have to torque it to one side to eliminate the play, and to keep the barrel from rising immediately upon squeezing the trigger. Slugs take longer than rifle bullets to get out of the barrel, so you don't want the shotgun to jump up when the slug is still in the barrel."
How you sight-in and practice with your shotgun should be based on how you anticipate shooting it during deer season, Clark says.
"After you make sure your scope is sighted-in accurately, you should take some practice shots in different positions to represent how you are likely to shoot it when in the woods or field after a deer," Clark says. "If you're one of the many Michigan hunters who is a stump sitter, practice shooting sitting down without a benchrest in front of you. If you prefer still-hunting or stalking and anticipate taking a deer from a standing position, you should definitely make sure you can drill a target while you're standing up and shooting freehand or steadying yourself against a tree."
Clark also offers some advice on picking slug loads, whether it's a rifled slug for smoothbore barrels or a sabot slug for rifled barrels.
"Don't overpower yourself," he says. "It's tempting to buy the most powerful slug loads you can find, but most of those are going to deliver a wallop to your shoulder and cheek with every shot, which can make them actually painful for target practice. That's especially true when you're trying to duplicate an actual hunting set-up and not using a shooting bench and weighted rifle rest."
He noted that plenty of mid-range loads with ample knockdown power are available to shotgunners.
"The important thing is to find a slug load that you're comfortable shooting and that you're confident about hitting the vitals of a deer with," he says.
One final bit of advice is know the distance to the deer you're going to shoot.
"Practice with a rangefinder so you can figure out how far an animal is so you can make an accurate shot," he says. "Shotgun slugs lose velocity and drop in a hurry, and even light side-winds can push them around when you're making a longer shot. I recommend that hunters use rifled barrels and the slimmer sabot slugs, which have less resistance in the air and are less affected by side winds. And until you've practiced and can get a good group at 100 yards, limit your shots at deer to 50 or 75 yards. That last 25 yards can make a big difference when it comes to accuracy and delivering a lethal shot."
For more information on Michigan hunting go to michigan.org. Click here to purchase a Michigan hunting license online.
Image by Dave Mull


text:
The Seattle Seahawks are still the clear favorite in leading the Associated Press power rankings, with commanding home-field advantage throughout the NFC playoffs there for the clinching with a couple of wins.
The San Francisco 49ers served notice, though, that they haven't disappeared. Thus, after a grind-it-out NFC West division victory by the 49ers over the Seahawks on Sunday, the top of the NFL is a little more crowded.
After two straight weeks as a unanimous first choice by the 12-member panel of media regularly covering the league, the Seahawks (11-2) received 10 first-place votes this time. The Denver Broncos (11-2) got the other two and came in second, in results released on Tuesday.
ESPN analyst Herm Edwards and ESPN.com reporter Jeff Legwold switched their first-place selections this week.
"Everyone needs to stop saying Peyton Manning can't play in the cold. The Broncos scored 51 points," Edwards wrote of Denver's lopsided win over the Tennessee Titans, the third 50-point game of the season by Manning and the Broncos.
The Seahawks lost their unmatched hold on the NFL's best record. Only 43 points separate them from the 49ers (9-4), who were fifth.
"Still may be the most balanced team the league has to offer at the moment," Legwold said.
The New Orleans Saints (10-3) moved back up two spots to third after a decisive victory over division foe Carolina. The New England Patriots (10-3) were fourth, following their third comeback win from a double-digit deficit in a row. Doing so again without star tight end Rob Gronkowski will be a difficult feat.
"The defense has been plagued with injuries and now Gronk is gone," wrote Pat Kirwan of CBSSports.com. "The only QB in the NFL that can keep this team winning is Tom Brady. This is the biggest test of his career."
The Panthers (9-4) were sixth and Kansas City (10-3) seventh. The Chiefs broke a three-game losing streak with a blowout win at Washington.
"Chiefs will be best No. 5 seed in the playoffs in a long time," said Fox consultant John Czarnecki.
Rounding out the top 10: Cincinnati Bengals (9-4), Philadelphia Eagles (8-5) and Indianapolis Colts (8-5), who were beaten 42-28 by the Bengals and have dropped three of their past five games, losing those by an average margin of more than 24 points.
"What has happened to the Colts?" wrote NBC analyst Tony Dungy of the team he used to coach.


text:
I think so.
This morning, while going through the tweets in my Twitter stream that had arrived overnight, I stumbled upon a MacObserver article that discussed the iPhone becoming the top "camera" on Flickr. (I have my own opinions on that factoid, which I left as a comment on that post; it's not a favorable commentary on Flickr users.) That post linked to a far more interesting one by Ted Landau titled "A Dozen Devices the iPhone is Killing." In it, Ted discusses how features in the iPhone that duplicate those in stand-alone devices are making those devices redundant or simply not necessary.
GPS for Everyday Use
As I commented on that post, Ted is right on target with the GPS analysis. I've been using various GPS tracking apps on my iPhone for a while now and am super-impressed with the results. The first one I tried was the $2 GPSTrack app, which I wrote about here. Since then, I've also played with GPSLite, a free app that does much the same and more for free (which an interface I find a bit too complex for everyday use). My goals with apps like these is to create track logs and trip computer data for flights and for geotagging photos.
Although I'm not fond of turn-by-turn navigation, I know there are plenty of apps that do this, too. So, as Ted pointed out, in-car GPS navigation systems can also be replaced by an iPhone.
GPS for Flying
For pilots, a great app called ForeFlight, which works on both iPhone and iPad, offers better functionality than the $12,000 panel-mount Garmin GPS in my helicopter. Rather than view my location on a primitive screen display, I can see it on an actual aeronautical chart. I can also download charts and other information in advance so there's no need to rely on 3G connectivity in flight. If I do have 3G connectivity, I can also get up-to-date weather information in flight. And although the iPhone screen is generally too small for my aging eyes to see the details, the same software works on my iPad — that screen size puts my panel mount system to shame. In fact, ForeFlight is the reason I'm updating to a G3 iPad 2 — that model includes a GPS; my original WiFi iPad does not.
Garmin is apparently trying to play catch-up with this functionality but I don't think they'll succeed. Why would someone pay thousands of dollars for a one-trick pony like a panel mount GPS when less than $700 will get you an iPad with GPS and Internet capabilities that can be updated on the fly and do so much more — for example, e-mail, Web browsing, ebook reader, and other apps? Best of all, the FAA is starting to accept apps like Foreflight as "electronic flight bags," thus making traditionally required documents such as printed charts and flight plans unnecessary. (This is something I hope to blog about in more detail soon.)
And Another Thing…
One thing Ted didn't mention is the main reason why I don't like carrying more devices than I have to: batteries and charging. When I go on the road, it seems that my "gadget kit" is filled with cables and charging devices. And spare batteries. What a pain in the butt! Wouldn't it be nicer to carry just one cable and charger, perhaps with a DC adapter? While it's true that running a GPS app on an iPhone, especially in tracking mode, sucks battery power more than almost anything else you're likely to do with the phone, a DC charging device can usually remedy this. Heck, even my helicopter has a DC power port.
At this point, it's hard to imagine why someone would buy a standalone GPS if they had an iPhone or another smartphone with equally good GPS capabilities. Can you think of a reason?


text:
Hillary Clinton battling to stay in White House raceApril 22nd, 2008 - 11:02 pm ICT by admin
By Arun Kumar
Washington, April 22 (IANS) Hillary Clinton was engaged in a do or die battle to keep her White House hopes alive as Democrats in Pennsylvania went to the polls Tuesday to choose their nominee in an increasingly bitter contest. The former first lady is favoured to win, but needs a convincing victory over frontrunner Barack Obama to cut into his lead in the overall delegate count and the popular vote. Obama leads her by 1,648 to 1,504 delegates, who pick the party nominee.
Polls close at 8 p.m. (5.30 a.m. IST Wednesday) with results expected shortly thereafter.
Unless she wins a substantial number of the 158 delegates at stake in Pennsylvania, Clinton would be hard put to win the support of superdelegates for her claim that she is the best candidate to face Republican John McCain in November's presidential election.
Neither candidate is expected to pick up the 2,025 delegates needed to win the Democratic nomination at the end of the primary season June 3. That would leave it to the Democratic superdelegates to decide the party nominee at a convention in late August.
Superdelegates are Democratic Party delegates or elected officials who can vote at the national convention. They choose their vote and are not required to commit to a particular candidate before the convention.
Clinton's one-time 20-point lead in the state has slipped to single digits in many polls amid an onslaught of advertisements by Obama, who has heavily outspent her in the first nominating contest in six weeks. Both camps tried to play down expectations ahead of the vote.
A CNN "poll of polls" of likely Pennsylvania Democratic primary voters calculated Monday shows Clinton leading Obama 50 percent to 43 percent with 7 percent unsure. The poll of polls is an average of three polls conducted by Zogby, Suffolk University and Quinnipiac University conducted April 18-20.
In the six weeks since the Mississippi primary, the Democratic race has taken on a particularly negative tone, with both candidates launching waves of robocalls, tough mailers and matching attack ads.
The two candidates also spent millions on television advertising. Since the beginning of the year, the Obama camp has spent over $8.5 million in television spots in the state, while the Clinton camp spent $3.6 million.
Calls for Clinton to drop out of the race have increased from within the party as the two candidates have stepped up attacks on each other. The increasingly pointed attacks have stoked fears among some Democratic leaders that the bruising primary battle could hurt Democratic chances in the general election.
"If Clinton wins by more than 10 points, which was her margin in neighboúring Ohio and New Jersey, her campaign will have new momentum and she will soldier on," said Bill Schneider, CNN senior political analyst. "If Clinton wins by single digits, we're in a political twilight zone. Nothing changes."
Clinton may be helped by the fact that Pennsylvania conducts "closed" primaries, meaning that only registered Democrats will be allowed to vote. Obama has benefited from the support of independent voters in previous primaries.
Clinton may also benefit from the fact that Pennsylvania has the second oldest population in the US, behind only Florida.
A Quinnipiac poll conducted April 18-20 has Clinton leading Obama 54 percent to 40 percent among voters 45 and over. Obama leads Clinton 57 percent to 41 percent among voters under the age of 45. The poll's margin of error was plus-or-minus 3.1 percentage points.
Obama is expected to do well in Philadelphia, which has a large African-American population, and the suburban counties surrounding Philadelphia, home to many upscale voters that in past primaries have tended to back the Illinois Democrat.
Clinton, on the other hand, is expected to do well in the more blue-collar city of Pittsburgh, located in western Pennsylvania, as well as the largely rural area in the middle of the state.
Pennsylvania will also hold a Republican primary, but as John McCain has already won the 1,191 delegates needed to get the party presidential nomination, it would be merely an academic exercise.


text:
you should try using a proxy server... may be that could solve your problem.see www.public*proxyserver*s.com for reference Regards, Upendra Jariya On Mon, Dec 22, 2008 at 3:16 PM, Carlos Tejo Alonso < firstname.lastname@example.com> wrote: > > Maybe I have express myself wrong. I will try again with an example: > > I am abroad, using a shared pc with arabic language as default. I send a > request to the URL http://www.example.org/doc. By content negociation, a > server will response with a page written in arabic. In that moment, I > want to change the language of the content, and the return page should > be again http://www.example.org/doc. > > What would be the correct approach ? > - a link that invokes a HTTP GET method > - a button that invokes a HTTP POST method > > Carlos Tejo Alonso > R&D and Innovation Department - CTIC Foundation [Asturias, Spain] > www.fundacionctic.org > >Received on Monday, 22 December 2008 11:27:47 UTC
This archive was generated by hypermail 2.3.1 : Tuesday, 6 January 2015 21:33:07 UTC