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Patent US20030017115 - Delivery of drug esters through an inhalation route - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe present invention relates to the delivery of drug esters through an inhalation route. Specifically, it relates to aerosols containing drug esters that are used in inhalation therapy. In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by...http://www.google.com/patents/US20030017115?utm_source=gb-gplus-sharePatent US20030017115 - Delivery of drug esters through an inhalation routeAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS20030017115 A1Publication typeApplicationApplication numberUS 10/146,516Publication dateJan 23, 2003Filing dateMay 13, 2002Priority dateMay 24, 2001Also published asCA2446904A1, CA2446916A1, CA2446916C, CA2446917A1, CA2446917C, CA2446990A1, CA2446990C, CA2447099A1, CA2447099C, CA2447166A1, CA2447166C, CA2447521A1, CA2447521C, DE60220909D1, DE60220909T2, DE60228232D1, DE60235851D1, DE60235852D1, EP1389094A1, EP1389094B1, EP1389095A1, EP1389096A1, EP1389096B1, EP1389096B9, EP1389097A1, EP1389097B1, EP1389098A1, EP1389098B1, EP1389099A1, EP1390021A1, EP1390021B1, EP1392257A1, EP1392257B1, EP1392259A2, EP1392259B1, EP1392261A2, EP1392261B1, EP1392262A1, EP1392264A1, EP1392264B1, EP1987823A1, EP1987823B1, EP1990046A1, EP1990046B1, US6716415, US6716416, US6716417, US6737042, US6740307, US6740308, US6740309, US6743415, US6776978, US6780399, US6780400, US6783753, US6797259, US6803031, US6805854, US6814954, US6814955, US6855310, US6884408, US6994843, US7005121, US7005122, US7008615, US7008616, US7011820, US7014840, US7014841, US7018620, US7022312, US7029658, US7033575, US7045118, US7048909, US7052679, US7052680, US7060254, US7063830, US7063831, US7063832, US7067114, US7070761, US7070762, US7070763, US7070764, US7070765, US7070766, US7078017, US7078018, US7078019, US7078020, US7087216, US7087217, US7094392, US7108847, US7115250, US7169378, US7442368, US7445768, US7449172, US7449174, US7449175, US7465435, US7465436, US7465437, US7468179, US7485285, US7491047, US7507397, US7507398, US7510702, US7524484, US7601337, US7988952, US8173107, US20030000518, US20030005924, US20030007933, US20030007934, US20030012737, US20030012740, US20030015189, US20030015190, US20030017114, US20030017116, US20030017117, US20030017118, US20030017119, US20030017120, US20030021753, US20030021754, US20030021755, US20030206869, US20040126326, US20040126327, US20040126328, US20040126329, US20040127481, US20040156788, US20040156789, US20040156790, US20040156791, US20040161385, US20040167228, US20040170569, US20040170573, US20040184996, US20040184997, US20040184998, US20040184999, US20040185000, US20040185001, US20040185002, US20040185004, US20040185005, US20040185006, US20040185007, US20040185008, US20040186130, US20040191179, US20040191180, US20040191181, US20040191182, US20040191183, US20040191184, US20040191185, US20040202617, US20040228807, US20050075273, US20050089479, US20060153779, US20060177382, US20060216243, US20060216244, US20060233719, US20060239936, US20060246011, US20060246012, US20060251587, US20060251588, US20060257329, US20060269487, US20060280692, US20060286042, US20060286043, US20070014737, US20070178052, US20080175796, US20090246147, WO2002094236A1, WO2002094236A9Publication number10146516, 146516, US 2003/0017115 A1, US 2003/017115 A1, US 20030017115 A1, US 20030017115A1, US 2003017115 A1, US 2003017115A1, US-A1-20030017115, US-A1-2003017115, US2003/0017115A1, US2003/017115A1, US20030017115 A1, US20030017115A1, US2003017115 A1, US2003017115A1InventorsJoshua Rabinowitz, Alejandro ZaffaroniOriginal AssigneeRabinowitz Joshua D., Zaffaroni Alejandro C.Export CitationBiBTeX, EndNote, RefManReferenced by (20), Classifications (140), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetDelivery of drug esters through an inhalation route
DETAILED DESCRIPTION OF THE INVENTION [0064] Definitions [0065] “Aerodynamic diameter” of a given particle refers to the diameter of a spherical droplet with a density of 1 g/mL (the density of water) that has the same settling velocity as the given particle. [0066] “Aerosol” refers to a suspension of solid or liquid particles in a gas. [0067] “Aerosol drug ester mass density” refers to the mass of drug ester per unit volume of aerosol. [0068] “Aerosol mass density” refers to the mass of particulate matter per unit volume of aerosol. [0069] “Aerosol particle density” refers to the number of particles per unit volume of aerosol. [0070] “Condensation aerosol” refers to an aerosol formed by vaporization of a substance followed by condensation of the substance into an aerosol. [0071] “Decomposition index” refers to a number derived from an assay described in Example 8. The number is determined by substracting the percent purity of the generated aerosol from 1. [0072] “Drug” refers to any chemical compound that is used in the prevention, diagnosis, treatment, or cure of disease, for the relief of pain, or to control or improve any physiological or pathological disorder in humans or animals. Such compounds are oftentimes listed in the Physician's Desk Reference (Medical Economics Company, Inc. at Montvale, N.J., 56th edition, 2002), which is herein incorporated by reference. [0073] “Drug acid” refers to a drug containing a carboxylic acid moiety. [0074] “Drug alcohol” refers to a drug containing a hydroxyl moiety. [0075] “Drug Ester” refers to a drug acid or drug alcohol, where the carboxylic acid group or hydroxyl group has been chemically modified to form an ester. The drug acids and alcohols from which the esters are formed come from a variety of drug classes, including, without limitation, antibiotics, anticonvulsants, antidepressants, antihistamines, antiparkinsonian drugs, drugs for migraine headaches, drugs for the treatment of alcoholism, muscle relaxants, anxiolytics, nonsteroidal anti-inflammatories, other analgesics, and steroids. [0076] Examples of antibiotics from which drug esters are formed include cefmetazole; cefazolin; cephalexin; cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins, such as cephalosporin c; cephalotin; cephamycins, such as cephamycin a, cephamycin b, and cephamycin c; cepharin; cephradine; ampicillin; amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin; benzylpenicillin; clometocillin; cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin; penicillins, such as penicillin n, penicillin o, penicillin s, and penicillin v; chlorobutin penicillin; dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin. [0077] Examples of anticonvulsants from which drug esters are formed include 4-amino-3-hydroxybutyric acid, ethanedisulfonate, gabapentin, and vigabatrin. [0078] Examples of antidepressants from which drug esters are formed include tianeptine and S-adenosylmethionine. [0079] Examples of antihistamines from which drug esters are formed include fexofenadine. [0080] Examples of antiparkinsonian drugs from which drug esters are formed include apomorphine, baclofen, levodopa, carbidopa, and thioctate. [0081] Examples of anxiolytics from which drug esters are formed include chlorazepate, calcium N-carboamoylaspartate and chloral betaine. [0082] Examples of drugs for migraine headache from which drug esters are formed include aspirin, diclofenac, naproxen, tolfenamic acid, and valproate. [0083] Examples of drugs for the treatment of alcoholism from which drug esters are formed include acamprosate. [0084] Examples of muscle relaxants from which drug esters are formed include baclofen. [0085] Examples of nonsteroidal anti-inflammatories from which drug esters are formed include aceclofenac, alclofenac, alminoprofen, amfenac, aspirin, benoxaprofen, bermoprofen, bromfenac, bufexamac, butibufen, bucloxate, carprofen, cinchophen, cinmetacin, clidanac, clopriac, clometacin, diclofenac, diflunisal, etodolac, fenclozate, fenoprofen, flutiazin, flurbiprofen, ibuprofen, ibufenac, indomethacin, indoprofen, ketoprofen, ketorolac, loxoprofen, meclofenamate, naproxen, oxaprozin, pirprofen, prodolic acid, salsalate, sulindac, tofenamate, and tolmetin. [0086] Examples of other analgesics from which drug esters are formed include bumadizon, clometacin, and clonixin. [0087] Examples of steroids from which drug esters are formed include betamethasone, chloroprednisone, clocortolone, cortisone, desonide, dexamethasone, desoximetasone, difluprednate, estradiol, fludrocortisone, flumethasone, flunisolide, fluocortolone, fluprednisolone, hydrocortisone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, pregnan-3-alpha-ol-20-one, testosterone, and triamcinolone. [0088] Examples of drug esters formed from drug acids include C1-C6 straight chain substituted or unsubstituted alkyl esters, C1-C6 branched chain substituted or unsubstituted alkyl esters, C3-C6 substituted or unsubstituted cyclic alkyl esters, C1-C6 substituted or unsubstituted alkenyl esters, C1-C6 substituted or unsubstituted alkynyl esters, and substituted or unsubstituted aromatic esters. C1-C6 straight chain unsubstituted alkyl esters include, for example, methyl ester, ethyl ester and propyl ester. C1-C6 straight chain substituted alkyl esters include, for example, 2-(dimethylamino)-ethyl ester (—CH2CH2N(CH3)2). C1-C6 branched chain unsubstituted alkyl esters include, for example, isopropyl ester and isobutyl ester. C1-C6 branched chain substituted alkyl esters include, for example, 2-(dimethylamino)-isopropyl ester (—CH(CH3)CH2N(CH3)2). C3-C6 unsubstituted cyclic alkyl esters include, for example, cyclopropyl and cyclohexyl ester. C3-C6 substituted cyclic alkyl esters include, for example, 2-(dimethylamino)-cyclopropyl ester. C1-C6 unsubstituted alkenyl esters include, for example, 2-butenyl ester (—CH2CHCHCH3). C1-C6 substituted alkenyl esters include, for example, 4-(dimethylamino)-2-butenyl ester (—CH2CHCHCH2N(CH3)2). C1-C6 unsubstituted alkynyl esters include, for example, 2-butynyl ester (—CH2CCCH3). C1-C6 substituted alkynyl esters include, for example, 4-(dimethylamino)-2-butynyl ester (—CH2CCCH2N(CH3)2). Unsubstituted aromatic esters include, for example, phenyl ester and naphthyl ester. Substituted aromatic esters include, for example, 4-(dimethylamino)phenyl ester. [0089] Examples of drug esters formed from drug alcohols include C1-C6 substituted or unsubstituted straight chain alkanoates, C1-C6 substituted or unsubstituted branched chain alkanoates, C1-C6 substituted or unsubstituted alkenoates, and C1-C6 substituted or unsubstituted alkynoates. C1-C6 unsubstituted straight chain alkanoates include, for example, methanoate (—C(O)H), ethanoate (—C(O)CH3) and propanoate (—C(O)CH2CH3). C1-C6 substituted straight chain alkanoates include, for example, 2-(phenyl)-ethanoate (—C(O)CH2Ph). C1-C6 unsubstituted branched chain alkanoates include, for example, isobutanoate (—C(O)CH(CH3)2). C1-C6 substituted branched chain alkanoates include, for example, 3-(phenyl)-isobutanoate (—C(O)CH(CH3)CH2Ph). C1-C6 unsubstituted alkenoates include, for example, 2-butenoate (—C(O)CHCHCH3). C1-C6 substituted alkenoates include, for example, 4-(phenyl)-2-butenoate (—C(O)CHCHCH2Ph). C1-C6 unsubstituted alkynoates include, for example, 2-butynoate (—C(O)CCCH3). C1-C6 substituted alkynoates include, for example, 4-(phenyl)-2-butynoate. [0090] Examples of other drug esters are found in U.S. Pat. No. 5,607,691 to Hale et al. and U.S. Pat. No. 5,622,944 to Hale et al. These patents are herein incorporated by reference. [0091] “Drug ester degradation product” refers to a compound resulting from a chemical modification of the drug ester. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis. [0092] “Inhalable aerosol drug ester mass density” refers to the aerosol drug ester mass density produced by an inhalation device and delivered into a typical patient tidal volume. [0093] “Inhalable aerosol mass density” refers to the aerosol mass density produced by an inhalation device and delivered into a typical patient tidal volume. [0094] “Inhalable aerosol particle density” refers to the aerosol particle density of particles of size between 100 nm and 5 microns produced by an inhalation device and delivered into a typical patient tidal volume. [0095] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to the aerodynamic diameter for which half the particulate mass of the aerosol is contributed by particles with an aerodynamic diameter larger than the MMAD and half by particles with an aerodynamic diameter smaller than the MMAD. [0096] “Norcholine ester” refers to an ester where the portion attached to the ester oxygen is —CH2CH2N(CH3)2. [0097] “Rate of aerosol formation” refers to the mass of aerosolized particulate matter produced by an inhalation device per unit time. [0098] “Rate of inhalable aerosol particle formation” refers to the number of particles of size between 100 nm and 5 microns produced by an inhalation device per unit time. [0099] “Rate of drug ester aerosol formation” refers to the mass of aerosolized, drug ester produced by an inhalation device per unit time. [0100] “Settling velocity” refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air. [0101] “Substituted” alkyl, alkenyl, alkynyl or aryl refers to the replacement of one or more hydrogen atoms on the moiety (e.g., alkyl) with another group. Such groups include, without limitation, the following: halo, amino, alkylamino, dialkylamino, hydroxyl, cyano, nitro and phenyl. [0102] “Typical patient tidal volume” refers to 1 L for an adult patient and 15 mL/kg for a pediatric patient. [0103] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase. The term “thermal vapor” refers to a vapor phase, aerosol, or mixture of aerosol-vapor phases, formed preferably by heating. [0104] Formation of Drug Esters from Drug Acids or Drug Alcohols [0105] Formation of drug esters from drug acids is typically accomplished by reacting the acid, or an activated derivative (e.g., acid chloride or mixed anhydride) with an appropriate alcohol under conditions well known to those of skill in the art. See, for example, Streitweiser, A., Jr. and Heathcock, C. H. (1981) Introduction to Organic Chemistry, Macmillan Publishing Col., Inc., New York. Conversely, formation of drug esters from drug alcohols is typically accomplished by reacting the alcohol with an appropriate activated acid derivative (e.g., ClC(O)CH3). See Id. [0106] Formation of Drug Ester Containing Aerosols [0107] Any suitable method is used to form the aerosols of the present invention. A preferred method, however, involves heating a composition comprising a drug ester to form a vapor, followed by cooling of the vapor such that it condenses to provide a drug ester comprising aerosol (condensation aerosol). The composition is heated in one of two forms: as pure active compound (i.e., pure drug ester); or, as a mixture of active compound and a pharmaceutically acceptable excipient. [0108] Pharmaceutically acceptable excipients may be volatile or nonvolatile. Volatile excipients, when heated, are concurrently volatilized, aerosolized and inhaled with drug ester. Classes of such excipients are known in the art and include, without limitation, gaseous, supercritical fluid, liquid and solid solvents. The following is a list of exemplary carriers within the classes: water; terpenes, such as menthol; alcohols, such as ethanol, propylene glycol, glycerol and other similar-alcohols; dimethylformamide; dimethylacetamide; wax; supercritical carbon dioxide; dry ice; and mixtures thereof. [0109] Solid supports on which the composition is heated are of a variety of shapes. Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness and virtually any shape permeated by small (e.g., less than 1.0 mm-sized) pores. Preferably, solid supports provide a large surface to volume ratio (e.g., greater than 100 per meter) and a large surface to mass ratio (e.g., greater than 1 cm2 per gram). [0110] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter). [0111] A number of different materials are used to construct the solid supports. Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite, porous carbons, carbon yarns and carbon felts; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well. [0112] Where aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina of defined surface area greater than 2 m2/g from Aldrich, St. Louis, Mo.) and a silicon wafer as used in the semiconductor industry. Carbon yarns and felts are available from American Kynol, Inc., New York, N.Y. Chromatography resins such as octadecycl silane chemically bonded to porous silica are exemplary coated variants of silica. [0113] The heating of the drug ester compositions is performed using any suitable method. Examples of methods by which heat can be generated include the following: passage of current through an electrical resistance element; absorption of electromagnetic radiation, such as microwave or laser light; and, exothermic chemical reactions, such as exothermic solvation, hydration of pyrophoric materials and oxidation of combustible materials. [0114] Delivery of Drug Ester Containing Aerosols [0115] Drug ester containing aerosols of the present invention are delivered to a mammal using an inhalation device. Where the aerosol is a condensation aerosol, the device has at least three elements: an element for heating a drug ester containing composition to form a vapor; an element allowing the vapor to cool, thereby providing a condensation aerosol; and, an element permitting the mammal to inhale the aerosol. Various suitable heating methods are described above. The element that allows cooling is, in it simplest form, an inert passageway linking the heating means to the inhalation means. The element permitting inhalation is an aerosol exit portal that forms a connection between the cooling element and the mammal's respiratory system. [0116] One device used to deliver the drug ester containing aerosol is described in reference to FIG. 1. Delivery device 100 has a proximal end 102 and a distal end 104, a heating module 106, a power source 108, and a mouthpiece 110. A drug ester composition is deposited on a surface 112 of heating module 106. Upon activation of a user activated switch 114, power source 108 initiates heating of heating module 106 (e.g, through ignition of combustible fuel or passage of current through a resistive heating element). The drug ester composition volatilizes due to the heating of heating module 106 and condenses to form a condensation aerosol prior to reaching the mouthpiece 110 at the proximal end of the device 102. Air flow traveling from the device distal end 104 to the mouthpiece 110 carries the condensation aerosol to the mouthpiece 110, where it is inhaled by the mammal. [0117] Devices, if desired, contain a variety of components to facilitate the delivery of drug ester containing aerosols. For instance, the device may include any component known in the art to control the timing of drug aerosolization relative to inhalation (e.g., breath-actuation), to provide feedback to patients on the rate and/or volume of inhalation, to prevent excessive use (i.e., “lock-out” feature), to prevent use by unauthorized individuals, and/or to record dosing histories. [0118] In Vivo Hydrolysis of Drug Esters [0119] After delivery of a drug ester aerosol to the lung of an animal, the ester moiety is typically hydrolyzed to provide the corresponding drug acid or drug alcohol, which produces a desired therapeutic effect. Where the ester reacts with water at ˜pH 7.4 at an appreciable rate, hydrolysis is chemically mediated. For other esters, hydrolysis is enzymatically mediated through the action of enzymes endogenous to the animal. [0120] Dosage of Drug Ester Containing Aerosols [0121] A typical dosage of a drug ester aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts). Where the drug ester is administered as a series of inhalations, a different amount may be delivered in each inhalation. The dosage amount of drug ester in aerosol form is generally no greater than twice the standard dose of the drug acid or drug alcohol given orally. [0122] One can determine the appropriate dose of drug ester containing aerosols to treat a particular condition using methods such as animal experiments and a dose-finding (Phase I/II) clinical trial. One animal experiment involves measuring plasma concentrations of drug acid or drug alcohol in an animal after its exposure to the aerosol. Mammals such as dogs or primates are typically used in such studies, since their respiratory systems are similar to that of a human. Initial dose levels for testing in humans is generally less than or equal to the dose in the mammal model that resulted in plasma drug levels associated with a therapeutic effect in humans. Dose escalation in humans is then performed, until either an optimal therapeutic response is obtained or a dose-limiting toxicity is encountered. [0123] Analysis of Drug Ester Containing Aerosols [0124] Purity of a drug ester containing aerosol is determined using a number of methods, examples of which are described in Sekine et al., Journal of Forensic Science 32:1271-1280 (1987) and Martin et al., Journal of Analytic Toxicology 13:158-162 (1989). One method involves forming the aerosol in a device through which a gas flow (e.g., air flow) is maintained, generally at a rate between 0.4 and 60 L/min. The gas flow carries the aerosol into one or more traps. After isolation from the trap, the aerosol is subjected to an analytical technique, such as gas or liquid chromatography, that permits a determination of composition purity. [0125] A variety of different traps are used for aerosol collection. The following list contains examples of such traps: filters; glass wool; impingers; solvent traps, such as dry ice-cooled ethanol, methanol, acetone and dichloromethane traps at various pH values; syringes that sample the aerosol; empty, low-pressure (e.g., vacuum) containers into which the aerosol is drawn; and, empty containers that fully surround and enclose the aerosol generating device. Where a solid such as glass wool is used, it is typically extracted with a solvent such as ethanol. The solvent extract is subjected to analysis rather than the solid (i.e., glass wool) itself. Where a syringe or container is used, the container is similarly extracted with a solvent. [0126] The gas or liquid chromatograph discussed above contains a detection system (i.e., detector). Such detection systems are well known in the art and include, for example, flame ionization, photon absorption and mass spectrometry detectors. An advantage of a mass spectrometry detector is that it can be used to determine the structure of drug ester degradation products. [0127] Particle size distribution of a drug ester containing aerosol is determined using any suitable method in the art (e.g., cascade impaction). An Andersen Eight Stage Non-viable Cascade Impactor (Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mock throat (USP throat, Andersen Instruments, Smyrna, Ga.) is one system used for cascade impaction studies. [0128] Inhalable aerosol mass density is determined, for example, by delivering a drug-containing aerosol into a confined chamber via an inhalation device and measuring the mass collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient. [0129] Inhalable aerosol drug ester mass density is determined, for example, by delivering a drug ester-containing aerosol into a confined chamber via an inhalation device and measuring the amount of non-degraded drug ester collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient. The amount of non-degraded drug ester collected in the chamber is determined by extracting the chamber, conducting chromatographic analysis of the extract and comparing the results of the chromatographic analysis to those of a standard containing known amounts of drug ester. [0130] Inhalable aerosol particle density is determined, for example, by delivering aerosol phase drug ester into a confined chamber via an inhalation device and measuring the number of particles of given size collected in the chamber. The number of particles of a given size may be directly measured based on the light-scattering properties of the particles. Alternatively, the number of particles of a given size is determined by measuring the mass of particles within the given size range and calculating the number of particles based on the mass as follows: Total number of particles=Sum (from size range 1 to size range N) of number of particles in each size range. Number of particles in a given size range=Mass in the size range/Mass of a typical particle in the size range. Mass of a typical particle in a given size range=π*D3*φ/6, where D is a typical particle diameter in the size range (generally, the mean boundary MMADs defining the size range) in microns, φ is the particle density (in g/mL) and mass is given in units of picograms (g−12) [0131] Rate of inhalable aerosol particle formation is determined, for example, by delivering aerosol phase drug ester into a confined chamber via an inhalation device. The delivery is for a set period of time (e.g., 3 s), and the number of particles of a given size collected in the chamber is determined as outlined above. The rate of particle formation is equal to the number of 100 nm to 5 micron particles collected divided by the duration of the collection time. [0132] Rate of aerosol formation is determined, for example, by delivering aerosol phase drug ester into a confined chamber via an inhalation device. The delivery is for a set period of time (e.g., 3 s), and the mass of particulate matter collected is determined by weighing the confined chamber before and after the delivery of the particulate matter. The rate of aerosol formation is equal to the increase in mass in the chamber divided by the duration of the collection time. Alternatively, where a change in mass of the delivery device or component thereof can only occur through release of the aerosol phase particulate matter, the mass of particulate matter may be equated with the mass lost from the device or component during the delivery of the aerosol. In this case, the rate of aerosol formation is equal to the decrease in mass of the device or component during the delivery event divided by the duration of the delivery event. [0133] Rate of drug ester aerosol formation is determined, for example, by delivering a drug ester containing aerosol into a confined chamber via an inhalation device over a set period of time (e.g., 3 s). Where the aerosol is pure drug ester, the amount, of drug collected in the chamber is measured as described above. The rate of drug ester aerosol formation is equal to the amount of drug ester aerosol collected in the chamber divided by the duration of the collection time. Where the drug ester containing aerosol comprises a pharmaceutically acceptable excipient, multiplying the rate of aerosol formation by the percentage of drug ester in the aerosol provides the rate of drug aerosol formation. [0134] Utility of Drug Ester Containing Aerosols [0135] The drug ester containing aerosols of the present invention are typically used for the same indication as the corresponding drug acid or drug alcohol. For instance, a drug ester of baclofen would be used to treat parkinsons disease and a drug ester of fexofenadine would be used to treat allergy symptoms. [0136] The following examples are meant to illustrate, rather than limit, the present invention. [0137] Drug acids or drug alcohols are typically commercially available from Simga (www.sigma-aldrich.com), obtained in tablet form from a pharmacy and extracted, or synthesized using well known methods in the art. EXAMPLE 1 General Procedures for Esterifying a Drug Acid [0138] Drug acid (10 mmol) is dissolved in 90 mL of dichloromethane. To the solution is added 1 drop of dimethylformamide and 13 mmol of oxalyl chloride. The resulting mixture is allowed to stir 30 min. The mixture is concentrated to dryness on a rotary evaporator to provide a residue, to which 50 mL of an alcohol (e.g., methanol) is added. The alcoholic solution is concentrated to dryness to afford the desired drug ester. [0139] Drug acid (6 mmol) is dissolved in 60 mL of dichloromethane. To the solution is added 1 drop of dimethylformamide and 9 mmol of oxalyl chloride. The resulting mixture is allowed to stir 1 h. The mixture is concentrated to dryness on a rotary evaporator to provide a residue, to which 47 mmol of an alcohol (e.g., HOCH2CH2N(CH3)2) in 20 mL dichloromethane is added. The reaction mixture is diluted with 60 mL dichloromethane and subjected to a series of washings: 50 mL saturated aqueous NaCl followed by 50 mL saturated aqueous NaHCO3 and 2× 50 mL saturated aqueous NaCl. The dichloromethane extract is dried over Na2SO4, filtered, and concentrated on a rotary evaporator to provide the desired drug ester. EXAMPLE 2 General Procedure for Esterifying a Drug Alcohol [0140] Drug alcohol (5 mmol) is dissolved in 50 mL of dichloromethane. To the solution is added 5.5 mmol Hunig's base and 10 mmol acetyl chloride. The reaction mixture is allowed to stir at room temperature for 1 hour. The mixture is washed with 50 mL saturated aqueous NaHCO3 followed by 50 mL saturated aqueous NaCl. The dichloromethane extract is dried over Na2SO4, filtered, and concentrated on a rotary evaporator to provide the desired drug ester. EXAMPLE 3 Procedure for Diesterifying Apomorphine [0141] Apomorphine.HCl.½H2O (300 mg) was suspended in 600 μL of acetic acid. The suspension was heated to 100° C. and then cooled to 50° C. Acetyl chloride (1 mL) was added to the suspension, which was heated at 40° C. for 3 h. The reaction mixture was allowed to cool to room temperature. Dichloromethane (1-2 mL) was added and the mixture was allowed to stir overnight. The reaction mixture was diluted with dichloromethane, and the solvent was removed on a rotary evaporator. Toluene (10 mL) was added to the residue and subsequently removed on a rotary evaporator. The toluene addition/removal was repeated. The resulting solid residue was triturated with ether, providing 430 mg of a solid (mp 158-160° C.). [0142] A portion of the solid (230 mg) was suspended in 50 mL of dichloromethane. The suspension was washed with saturated aqueous NaHCO3. The dichloromethane layer was dried over Na2SO4, filtered and concentrated on a rotary evaporator to provide 190 mg of the desired free base (mp ˜110° C.). EXAMPLE 4 Procedure for Synthesis of 2-(N,N-Dimethylamino)Ethyl Ester of Ketorolac [0143] Ketorolac (255 mg), triethylamine (101 mg) and 2-(dimethylamino)ethanol (HOCH2CH2N(CH3)2, 380 mg) were added to 2 mL dichloromethane. The mixture was cooled to −25° C. to −20° C. for 15 min. BOP (464 mg) was added, and the reaction mixture was gradually allowed to warm to room temperature. See Kim, M. H. and Patel, D. V. (1994) Tet. Lett. 35: 5603-5606. The reaction mixture was diluted with 60 mL of dichloromethane and washed sequentially with saturated aqueous NaCl, saturated aquesous NaHCO3 and then saturated aqueous NaCl. The dichloromethane extract was dried over Na2SO4, filtered, and concentrated on a rotary evaporator to provide 390 mg of the desired material. EXAMPLE 5 General Procedure for Volatilizing Compounds from Halogen Bulb [0144] A solution of drug in approximately 120 μL dichloromethane is coated on a 3.5 cm×7.5 cm piece of aluminum foil (precleaned with acetone). The dichloromethane is allowed to evaporate. The coated foil is wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, Calif.), which is inserted into a glass tube sealed at one end with a rubber stopper. Running 60 V of alternating current (driven by line power controlled by a variac) through the bulb for 5-12 s or 90 V for 2.5-3.5 s affords thermal vapor (including aerosol), which is collected on the glass tube walls. (When desired, the system is flushed through with argon prior to volatilization.) Reverse-phase HPLC analysis with detection by absorption of 225 nm light is used to determine the purity of the aerosol. [0145] Table 1, which follows, provides data from drugs volatilized using the above-recited general procedure. TABLE 1 AEROSOL COMPOUND AEROSOL PURITY MASS Indomethacin Methyl Ester 99% 1.44 mg Indomethacin Ethyl Ester >99% 3.09 mg Indomethacin Norcholine Ester 100% 2.94 mg Ketoprofen Methyl Ester 99% 4.4 mg Ketoprofen Ethyl Ester 99.65% 4.11 mg Ketoprofen Norcholine Ester 100% 2.6 mg Ketorolac Methyl Ester 100% 3.17 mg Ketorolac Ethyl Ester >99% 5.19 mg Ketorolac Norcholine Ester 100% 1.64 mg Apomorphine Diacetate-HCl 94% 1.65 mg Apomorphine Diacetate 96.9% 2.03 mg EXAMPLE 6 General Procedure for Hydrolysis Studies of Drug Esters [0146] Drug ester (20 μL, 10 mM acetonitrile) is added to 1 mL PBS solution (pH 7.5) at room temperature. At intermittent time points, an aliquot of the resulting mixture is injected into an HPLC to obtain the ratio of drug ester to drug acid or drug alcohol. An Arrhenius plot of the data provides a t1/2 for hydrolysis. Table 2 below provides t1/2 values for a variety of compounds. TABLE 2 COMPOUND t1/2 Ketoprofen Methyl Ester >48 h Ketoprofen Ethyl Ester >48 h Ketoprofen Norcholine Ester 315 min. Ketorolac Methyl Ester >48 h Ketorolac Ethyl Ester >48 h Ketorolac Norcholine Ester 14 min Indomethacin Methyl Ester >48 h Indomethacin Ethyl Ester >48 h Indomethacin Norcholine Ester 315 min. Apomorphine Diacetate >48 h EXAMPLE 7 General Procedure for Human Serum Hydrolysis Studies of Drug Esters [0147] Human serum (2.34 mL) is placed in a test tube. To the serum is added 260 μL of a 10 mM solution of drug ester in acetonitrile. The tube is placed in a 37° C. incubator, and at various time points a 500 μL aliquot is removed. The aliquot is mixed with 500 μL methanol, and the mixture is vortex mixed and centrifuged. A sample of the supernatant is analyzed by HPLC obtain the ratio of drug ester to drug acid or drug alcohol. An Arrhenius plot of the data provides a t1/2 for hydrolysis. Table 3 below provides t1/2 values for a variety of compounds. TABLE 3 COMPOUND t1/2 Ketoprofen Methyl Ester 144 min Ketoprofen Ethyl Ester 224 min Ketoprofen Norcholine 37 s Ester Ketorolac Ethyl Ester 90 min Ketorolac Norcholine Ester 13 s Indomethacin Methyl Ester >48 h Indomethacin Ethyl Ester >48 h Indomethacin Norcholine 23 min Ester Apomorphine Diacetate 76.2 s EXAMPLE 8 General Procedure for Screening Drug Esters for Aerosolization Preferability [0148] Drug ester (1 mg) is dissolved or suspended in a minimal amount of a suitable solvent (e.g., dichloromethane or methanol). The solution or suspension is pipeted onto the middle portion of a 3 cm by 3 cm piece of aluminum foil. The coated foil is wrapped around the end of a 1 ½ cm diameter vial and secured with parafilm. A hot plate is preheated to approximately 300° C., and the vial is placed on it foil side down. The vial is left on the hotplate for 10 s after volatilization or decomposition has begun. After removal from the hotplate, the vial is allowed to cool to room temperature. The foil is removed, and the vial is extracted with dichloromethane followed by saturated aqueous NaHCO3. The organic and aqueous extracts are shaken together, separated, and the organic extract is dried over Na2SO4. An aliquot of the organic solution is removed and injected into a reverse-phase HPLC with detection by absorption of 225 nm light. A drug ester is preferred for aerosolization where the purity of the drug ester aerosol isolated by this method is greater than 85%. Such a drug ester has a decomposition index less than 0.15. The decomposition index is arrived at by subtracting the percent purity (i.e., 0.85) from 1. Referenced byCiting PatentFiling datePublication dateApplicantTitleUS7011820Apr 1, 2004Mar 14, 2006Alexza Pharmaceuticals, Inc.Delivery of compounds for the treatment of Parkinsons through an inhalation routeUS7014841Mar 31, 2004Mar 21, 2006Alexza Pharmaceuticals, Inc.Delivery of antiemetics through an inhalation routeUS7018620Feb 9, 2004Mar 28, 2006Alexza Pharmaceuticals, Inc.Delivery of beta-blockers through an inhalation routeUS7048909Feb 9, 2004May 23, 2006Alexza Pharmaceuticals, Inc.Delivery of beta-blockers through an inhalation routeUS7052680Apr 1, 2004May 30, 2006Alexza Pharmaceuticals, Inc.Delivery of compounds for the treatment of Parkinsons through an inhalation routeUS7063832Mar 31, 2004Jun 20, 2006Alexza Pharmaceuticals, Inc.Delivery of muscle relaxants through an inhalation routeUS7108847Mar 31, 2004Sep 19, 2006Alexza Pharmaceuticals, Inc.Delivery of muscle relaxants through an inhalation routeUS7645442Aug 4, 2003Jan 12, 2010Alexza Pharmaceuticals, Inc.Rapid-heating drug delivery article and method of useUS20040096402 *Oct 30, 2003May 20, 2004Alexza Molecular Delivery CorporationDelivery of aerosols containing small particles through an inhalation routeUS20040099269 *Nov 20, 2003May 27, 2004Alexza Molecular Delivery CorporationDrug condensation aerosols and kitsUS20040156791 *Dec 30, 2003Aug 12, 2004Alexza Molecular Delivery CorporationDelivery of antipsychotics through an inhalation routeUS20040161385 *Feb 9, 2004Aug 19, 2004Alexza Molecular Delivery CorporationDelivery of beta-blockers through an inhalation routeUS20040184996 *Jan 27, 2004Sep 23, 2004Alexza Molecular Delivery CorporationDelivery of nonsteroidal antiinflammatory drugs through an inhalation routeUS20040184998 *Jan 29, 2004Sep 23, 2004Alexza Molecular Delivery CorporationDelivery of drug esters through an inhalation routeUS20040185002 *Jan 30, 2004Sep 23, 2004Alexza Molecular Delivery CorporationDelivery of physiologically active compounds through an inhalation routeUS20040204439 *Apr 14, 2003Oct 14, 2004Staniforth John NicholasComposition, device, and method for treating sexual dysfunction via inhalationUS20040228807 *Jan 27, 2004Nov 18, 2004Alexza Molecular Delivery CorporationDelivery of sedative-hypnotics through an inhalation routeUS20050075273 *Dec 30, 2003Apr 7, 2005Alexza Molecular Delivery CorporationDelivery of opioids through an inhalation routeUS20050089479 *Dec 30, 2003Apr 28, 2005Alexza Molecular Delivery CorporationDelivery of sedative-hypnotics through an inhalation routeUS20060178394 *Apr 14, 2004Aug 10, 2006Staniforth John NPharmaceutical compositions comprising apomorphine for pulmonary inhalation* Cited by examinerClassifications U.S. Classification424/46, 514/295, 514/420International ClassificationA61K31/5415, A61P25/22, A61K31/13, A61K31/439, A61P25/18, A61K31/4045, C07D487/04, A61K31/485, A61K31/4525, A61K9/72, A61P25/32, A61P25/08, A61K9/12, A61P25/24, A61K31/421, A61M11/00, A61K31/4985, A61K31/505, A61P25/16, A61P37/08, A61K31/53, A61K31/519, A61P25/20, A61K31/495, A61P43/00, C07D471/04, A61K31/192, A61K31/4402, A61K31/437, A61K31/4545, A61P15/10, A61K31/407, A61K31/46, A61P31/04, A61K31/48, A61K31/4418, A61P29/00, A61K31/55, A61K31/19, A61K31/5513, A61P21/02, A61K31/403, A61K31/40, A61K31/167, A61K45/00, A61K31/405, A61P25/06, A61K31/404, A61K31/423, A61K31/551, A61K9/00, A61K31/496, A61K47/48, A61K31/137, A61K31/473, A61K31/165, A61K31/501, A61K31/00, A61K31/49, F24J1/00, A61K31/5517, A61K31/422, A61K31/216, A61K31/27, A61K31/4196, A61K31/138Cooperative ClassificationY10S514/923, Y10S514/958, A61K31/27, A61K31/00, A61K31/405, A61K31/192, A61K31/165, A61K31/49, A61K31/485, A61K31/4985, A61K9/0073, A61K31/195, A61K31/216, A61K31/407, A61K31/423, A61K31/501, A61K31/519, A61K9/007, A61K31/5517, A61K31/404, A61K31/496, A61K31/437, A61K9/12, A61K31/422, A61K31/421, A61K31/4196, A61K31/473, A61K31/137, A61K31/53, A61K31/551, A61K31/19, F24J1/00, A61K47/48023, A61K31/138, A61K31/495, A61M2205/8206, A61M15/06, A61M11/042European ClassificationA61K31/53, A61K31/00, A61K31/195, A61K31/19, A61K31/421, A61K31/485, A61K31/4985, A61K31/49, A61K31/404, A61K9/00M20, A61K31/501, A61K47/48H4, A61K31/137, A61K31/551, A61K31/437, F24J1/00, A61K31/138, A61K9/12, A61K31/405, A61K31/27, A61K31/422, A61K31/165, A61K31/519, A61K31/495, A61K31/423, A61K31/5517, A61K31/216, A61K9/00M20B, A61K31/192, A61K31/407, A61K31/473, A61K31/496, A61K31/4196Legal EventsDateCodeEventDescriptionSep 17, 2002ASAssignmentOwner name: ALEXZA MOLECULAR DELIVERY CORPORATION, CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RABINOWITZ, JOSHUA D.;ZAFFARONI, ALEJANDRO C.;REEL/FRAME:013294/0594;SIGNING DATES FROM 20020823 TO 20020911Oct 18, 2005ASAssignmentOwner name: ALEXZA PHARMACEUTICALS, INC., CALIFORNIAFree format text: CHANGE OF NAME;ASSIGNOR:ALEXZA MOLECULAR DELIVERY CORPORATION;REEL/FRAME:016926/0674Effective date: 20050720Sep 20, 2007FPAYFee paymentYear of fee payment: 4Jan 2, 2012REMIMaintenance fee 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Patent US4665730 - Method of controlling product tension in a rolling mill - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsIn a rolling mill wherein product is rolled continuously in successive first and second blocks at the finishing end of the mill, a pinch roll unit is interposed between the two blocks. The motor speed of the pinch roll unit is employed in combination with other variables to preset the motor speed of...http://www.google.com/patents/US4665730?utm_source=gb-gplus-sharePatent US4665730 - Method of controlling product tension in a rolling millAdvanced Patent SearchPublication numberUS4665730 APublication typeGrantApplication numberUS 06/785,724Publication dateMay 19, 1987Filing dateOct 9, 1985Priority dateOct 9, 1985Fee statusLapsedAlso published asCA1279712C, DE3670222D1, EP0219316A2, EP0219316A3, EP0219316B1Publication number06785724, 785724, US 4665730 A, US 4665730A, US-A-4665730, US4665730 A, US4665730AInventorsEndre S. MarotiOriginal AssigneeMorgan Construction CompanyExport CitationBiBTeX, EndNote, RefManPatent Citations (2), Referenced by (9), Classifications (15), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetMethod of controlling product tension in a rolling mill
US 4665730 AAbstract
In a rolling mill wherein product is rolled continuously in successive first and second blocks at the finishing end of the mill, a pinch roll unit is interposed between the two blocks. The motor speed of the pinch roll unit is employed in combination with other variables to preset the motor speed of the second block prior to entry of the product front end therein. The preset motor speed of the second block produces an acceptable level of interblock product tension once the product has entered the second block. Thereafter, product elongation in the first block is monitored and required adjustments to the motor speed of the second block are made in order to maintain interblock product tension within acceptable limits.
1. In a rod rolling mill wherein steel is hot rolled to a semi-finished product in a first block driven by a first motor means, and the semi-finished product is quenched before being rolled to a finished product in a second block driven by a second motor means, a method of controlling the operating speed of said second motor means in order to maintain an acceptable level of interblock product tension while the product is being continuously rolled in both of said blocks, said method comprising:(a) rolling the semi-finished product through a pinch roll unit interposed between said first and second blocks, said pinch roll unit being driven by a third motor means; (b) after the product front end has cleared said pinch roll unit, and while it is in a zero tension condition prior to entering into said second block, measuring at least the following:S1 =operating speed of said first motor means; S2 =operating speed of said second motor means; S3 =operating speed of said third motor means; Ae =entering product cross sectional area at said first block; Ax =exiting product cross sectional area at said block; (c) comparing S2 and S3, and based on this comparison, making any required adjustment to the operating speed S2 of said second motor means prior to the entry of the product front end into said second block in order to produce an acceptable level of product tension in that section of the product passing between said blocks after the product has entered the second block and is being continuously rolled in both blocks; (d) based on the measurements of (b), calculating and storing the following values:e=(Ae)�(Ax)=total elongation in said first block; Rv =(S1)�(S3)=ratio value of drive motor speeds of said first block and said pinch roll unit; Vt =(Ax)�(S3)=Volume per unit of time of product exiting from said first block; (e) after entry of the product in said second block, repeating the measurements of (b) and based on said repeated measurements, recalculating the values of (d); (f) determining if unacceptable variations exist between the recalculated value of e and the previously stored values of e; and (g) if such an unacceptable variation exists and is attributable to an improper level of interblock product tension and not to unacceptable variations in Rv or V/t, adjusting the operating speed S2 of said second motor means to correct the level of interblock product tension and thereby bring the value of e to within acceptable limits with reference to the previously stored value of (e). 2. In a rod rolling mill wherein steel is hot rolled to a semi-finished product in a first block driven by a first motor means before being rolled to a finished product in a second block driven by a second motor means, a method of controlling the operating speed of said second motor means in order to maintain an acceptable level of interblock product tension while the product is being continuously rolled in both of said blocks, said method comprising:(a) rolling the semi-finished product through a pinch roll unit interposed between said first and second blocks, said pinch roll unit being driven by a third motor means; (b) after the product front end has cleared said pinch roll unit, and while it is in a zero tension condition prior to entering into said second block, measuring at least the following:S1 =operating speed of said first motor means; S2 =operating speed of said second motor means; S3 =operating speed of said third motor means; and (c) comparing S2 and S3 and based on said comparison, making any required adjustment to the operating speed S2 of said second motor means prior to the entry of the product front end into said second block in order to produce an acceptable level of product tension in that section of the product passing between said blocks after the product has entered said second block and is being continuously rolled in both blocks. Description
This invention relates generally to continuous rolling mills of the type which thermo-mechanically treat products such as steel rods, and is concerned in particular with an improvement in the speed regulation of such mills.
Thermo-mechanical treatment in a rod mill usually entails hot rolling a product through conventional roughing and intermediate stands and then through a first block to produce a semi-finished round. The semi-finished round is then passed through one or more water boxes where it is subjected to an in line water quench to a surface temperature of about 500� C. before being finish rolled in a second block. As herein employed, the term "block" refers to a plurality of mechanically interconnected rolling stands driven by a common drive which usually consists of single or tandem variable speed electric motors.
While the product is being rolled continuously in both the first and second blocks, the tension in that portion of the product passing between the blocks must be carefully controlled. Too little tension may cause the product to buckle and possibly cobble whereas excessive tension will adversely affect tolerances. Ideally, the product will be maintained under slight substantially constant tension as it is being rolled in both blocks. In order to do this, however, the motor speeds of the first and second blocks must be precisely coordinated.
In the past, attempts have been made at maintaining the required level of interblock product tension by monitoring and controlling the motor speeds of the block drives. While such systems are marginally adequate for relatively slow speed rolling operations, they are incapable of operating effectively under high speed rolling conditions, e.g., where the speed of the product passing between the blocks is at or above 50 m/sec.
The major problem with the conventional control systems is that they lack a true speed reference for the product passing from the first block to the second block. Drive motor speeds are not reliable indicators of true product speed because of the forward slip experienced by the product during the rolling operation.
In the method and system of the present invention, a pinch roll unit is interposed between the first and second blocks. As herein employed, the term "pinch roll unit" refers to a driven pair of rolls arranged to grip the product without deforming or reducing the product cross section to any significant degree. There is, accordingly, no appreciable forward slip in the pinch roll nip, which means that the motor speed of the pinch roll drive can be relied upon as an accurate indication of true product speed. According to the present invention, prior to the arrival of the product front end at the second block, the following measurements are taken:
Ae =Cross sectional area of product entering first block.
Ax =Cross sectional area of product exiting from first block.
S1 =Drive motor speed of first block.
S3 =Drive motor speed of pinch roll unit.
Based on these measurements, the following calculations are made:
e=(Ae)�(Ax)
Rv =(S1)�(S3)
V/t=(Ax)�(S3)
e=total product elongation in the first block.
Rv =ratio value of drive motor speeds of first block and pinch roll unit.
V/t =Volume per unit of time of product exiting from first block.
The values of e, Rv and V/t are stored and S3 is employed to preset the drive motor speed S2 of the second block. At this time, the product is in a "zero tension condition" because it has yet to enter into and is thus unaffected by the rolling action of the second block. S2 will be preset to produce a slight interblock tension in the product after it has entered the second block and is being continuously rolled in both blocks. As herein employed, the term "slight tension" means that level of tension which will insure smooth passage of the product between the two blocks without adversely affecting the cross sectional area of the product exiting from the first block.
After entry of the product in the second block, the above listed measurements and calculations are repeated, and the resulting values of e, Rv and V/t are compared with the stored zero tension condition values. If an unacceptable variation in e is detected, and if that variation is attributable to interblock product tension and not to unacceptable variations in either Rv or V/t, then an adjustment is made to S2 to adjust interblock product tension and thereby bring e within acceptable limits.
FIG. 1 is a schematic illustration of a rod mill arrangement in accordance with the present invention; and
FIG. 2 is a flow chart of a typical embodiment of system software.
Referring initially to FIG. 1, the finishing end of a steel rod rolling mill is shown as including a first block B1 driven by a first motor means M1. As herein employed, the term "motor means" means variable speed electric motors employed either singly or in tandem combinations. The first block is adapted to roll a round received from a preceding conventional arrangement of roughing and intermediate stands (not shown). The product emerges from the first block in a semi-finished state, and is then directed through one or more water cooling boxes 10 before being rolled to a finished product in a second block B2 driven by a second motor means M2. From here, the finished product is directed to a laying head 12 where it is formed into rings 14. The rings are deposited in an overlapping offset pattern on a conveyor 16, and after undergoing further cooling on the conveyor, are eventually gathered into coils at a reforming station (not shown).
The blocks B1 and B2 can be of any conventional design, such as for example that shown in U. S. Pat. No. Re.28,107. The laying head 12, water boxes 10 and conveyor 16 are also standard pieces of equipment well known to those skilled in the art.
In a typical rolling mill operation producing 5.5 mm. thermomechanically treated steel rod at a delivery speed of about 100 m.sec., the product will enter the first block B1 at a speed of about 11 m/sec., with a temperature of about 850 � C. and a cross sectional area Ae of about 240 mm2. The product will exit from the first block at a speed of at least about 50 m/sec. and at a temperature of at least about 850� C. with a cross sectional area Ax of about 38 mm2. As the product passes through the water boxes 10, it will be cooled to a reduced temperature of below about 500� C. before entering the second block B2. The rolling action of the second block will produce a finished cross section which ideally will have the desired 5.5 mm. diameter and an area of 23.76 mm2.
In order to insure that the product experiences a smooth transition between the first and second blocks B1, B2, the speed of the second block's motor means M2 is adjusted to produce a slight interblock tension in the product, e.g., approximately 0.2 Kg/mm2. In order to maintain this level of tension, the M2 speed regulation must be extremely precise, preferably to within �0.1% error max.
In order to achieve this objective, and in accordance with the present invention, a gauge 18 is positioned in advance of the first block B1 to measure the entering product cross sectional area Ae and another gauge 20 is similarly positioned after the first block to measure the exiting product cross sectional area Ax. A pinch roll unit PR is located between the two blocks B1 and B2. The pinch roll unit is driven by a third motor means M3. As previously indicated, the pinch roll unit is designed to grip the product without deforming or reducing its cross section to any significant degree.
The operating speeds S1, S2, S3 of the first, second and third motor means M1, M2 and M3 are measured by tachometers 22. The outputs of the tachometers 22 and the gauges 20, 18 are fed to a micro processor MP, and a control signal Cs from the micro processor is used to control the speed of the second motor means M2 driving the second block B2.
With reference now to FIG. 2, which is a control program flow diagram for the system of FIG. 1, beginning at 30 and based on the outputs of gauges 18 and 20, a decision is made as to whether the product has passed through the first block B1. If it has not, the program recycles from START. If it has, then as indicated at 32 and 34, the entry and exit areas Ae, Ax are obtained and as indicated at 36, the elongation e in the first block B1 is calculated. Then, as indicted at 38, a decision is made as to whether the product has arrived at the pinch roll unit PR. If it has not, the program recycles from START. If it has, then as indicated at 40, 42 and 44, the motor speeds S1, S3 of the first block B1 and pinch roll unit PR and the exiting area Ax from the first block are measured. As indicated at 46 and 48, these measurements are used to calculate the volume of metal per unit of time V/t exiting from the first block B1 and the ratio value Rv of motor speeds S1 and S3.
Then, as indicated at 50, a decision is made as to whether the product has entered the second block B2. If it has not, then a zero tension condition exists between the two blocks B1 and B2, and as indicated at 52, the values for v/t, Rv and e are stored, and as indicated at 54, an output signal (Cs in FIG. 1) based on the drive motor speed S3 of the pinch roll unit is used to preset the drive motor speed S2 of the second block B2. This preset speed is intended to produce the previously mentioned slight interblock tension of approximately 0.2 Kg/,2. The program then recycles from START.
As indicated at 56, once the product is in the second block B2, the Rv, V/t and e calculations are compared with the zero tension condition stored values. As indicated at 58, a decision is then made as to whether the values are within predetermined limits. If they are, the program recycles from START.
However, if this comparison indicates that one or more of the calculated Rv, Vt and e values do not compare favorably with the stored zero tension condition values, then as indicated at 60, a determination must be made as to what if any corrective action is required. For example, if the product elongation e in the first block B1 has undergone an unacceptable change, and this change is attributable to interblock tension and not to variations in Rv or Vt, then as indicated at 62, the speed S2 of the second block's drive motor M2 is adjusted to correct the level of interblock tension. On the other hand, if the change in elongation is attributable to changes in Rv and/or Vt, the speed S2 of drive motor M2 will remain unchanged and appropriate messages will be displayed to operating personnel to indicate that other mill adjustments are required. Such other adjustments might, for example, include roll parting adjustments in the first block B1 or in the intermediate mill.
In light of the foregoing, it will now be appreciated by those skilled in the art that the operating speed S3 of the pinch roll drive motor M3 provides a valuable and heretofore unobtainable insight into the rolling conditions in and between the first and second blocks B1, B2. More particularly, the value of S3, which as previously noted is a reliable indicator of true product speed, is useful to preset the operating speed S2 of the second block's drive motor M2 before the product arrives at the second block. This anticipatory action obviates problems that might otherwise occur if the product front end were to be allowed to enter the second block B2 under conditions where the motor speeds S1, S2 were dangerously mismatched.
The value of S3 also provides a more accurate basis for calculating the volume per unit time V/t of product exiting from the first block B1. This in turn helps to identify the causes of unacceptable variations in interblock tension other than that that might be due to an improper setting of the second block's drive motor speed.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS3964938 *Jan 20, 1975Jun 22, 1976New York Wire Mills CorporationMethod and apparatus for forming high tensile steel from low and medium carbon steelUS4306440 *Feb 14, 1980Dec 22, 1981Friedrich Kocks Gmbh & Co.Methods and apparatus for rolling bars, rods and wire* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS5406822 *Mar 5, 1993Apr 18, 1995Sms Schloemann-Siemag AktiengesellschaftLight-section wire millUS5421183 *Aug 31, 1994Jun 6, 1995Sms Schloemann-Siemag AgLight-section wire millUS5784914 *Aug 2, 1996Jul 28, 1998Ceda Spa Costruzioni Elettromeccaniche E Dispositivie D'automazioneMethod to control between rolling stands the drawing of the rolled stock and relative deviceUS5791182 *Aug 2, 1996Aug 11, 1998Ceda Spa Costruzioni Elettromeccaniche E Dispositivi D'automazioneMethod to control between rolling stands the drawing of the rolled stock and relative deviceUS6568232 *Jul 9, 1999May 27, 2003Abb AbMethod and a device for controlling the dimensions of an elongated material rolled in a rolling millUS7578155 *Mar 26, 2007Aug 25, 2009Sms Meer GmbhWire-rolling stand and method of operating sameUS7617711 *Dec 1, 2005Nov 17, 2009Sms Meer GmbhMethod of controlling the cross section of a wire rod strand emerging from a wire rod mill lineEP1074318A2 *Jul 8, 2000Feb 7, 2001SMS Demag AGMethod for controlling the tension of the wire between the finishing block and the following block in wire rolling millsEP1669141A1 *Oct 15, 2005Jun 14, 2006SMS Meer GmbHProcess for the control of the cross-section of wires running out from a wire rolling mill and metal wire rolling mill* Cited by examinerClassifications U.S. Classification72/205, 72/8.8, 72/9.5International ClassificationB21B37/00, B21B1/18, B21B39/00, B21B37/48, B21B45/02, B21B37/52Cooperative ClassificationB21B37/52, B21B45/0224, B21B1/18, B21B2275/04, B21B39/006European ClassificationB21B37/52Legal EventsDateCodeEventDescriptionJul 13, 1999FPExpired due to failure to pay maintenance feeEffective date: 19990519May 16, 1999LAPSLapse for failure to pay maintenance feesDec 8, 1998REMIMaintenance fee reminder mailedOct 21, 1994FPAYFee paymentYear of fee payment: 8Nov 15, 1990FPAYFee paymentYear of fee payment: 4Oct 9, 1985ASAssignmentOwner name: MORGAN CONSTRUCTION COMPANY, 15 BELMONT STREET, WOFree format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:MAROTI, ENDRE S.;REEL/FRAME:004477/0645Effective date: 19851004RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services


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Milo R. DePhillips
Milo R. DePhillips Des Moines - Milo Rudolph DePhillips was born September 7, 1931, in Des Moines, Iowa, to Nick and Mary Ann (Lucia) DePhillips. He proudly served his country in the United States Army and was...
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Lillian C. Lyle Des Moines - Lillian C. Lyle was born February 8, 1951, in Des Moines, Iowa, to Arnold Jr. and Ethel (Spivey) Lyle. She was a proud veteran of the U. S. Navy. Lillian passed away Wednesday, December...
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MarySue McMulin Des Moines - MarySue Effie McMulin, 71, passed away peacefully January 10, 2018, while under hospice care in Cedar Rapids. Funeral service will be held on Wednesday, January 17, 2018, at Hamilton's...
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Delores Kingery
Delores Kingery Des Moines - Delores Jean (Stanley) Kingery, age 80, passed away peacefully Thursday, January 11, 2018, at Taylor House Hospice in Des Moines. Delores was born October 14, 1937. She was one of 18...
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Velma Blanchard Des Moines - Velma Blanchard, 80, was a strong woman and she was a fighter until the end. She passed away peacefully Thursday, January 11, 2018, with her family by her side. Funeral service will begin...
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Charles Michael Mincks Of Des Moines, Iowa - Charles "Charlie" Mincks, age 82, passed away on Monday, January 8, 2018 at Mercy Hospice. Charlie was born on April 22, 1935 in Hiteman, IA. Charlie proudly served his...
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Charles passed away in January 2018. Charles was a resident of Iowa at the time of passing.
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Patricia Ann Woods Of Des Moines - Passed away on 1/5/18 at the age of 59. Visitation will be 5 to 8 p.m., 1/11/18, at Hamilton's Funeral Home, 605 Lyon Street. Funeral services will be held 11 a.m., 1/12/18, at...
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Patricia passed away in January 2018. Patricia was a resident of Iowa at the time of passing.
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Leland D. Young Des Moines - Leland Duane Young, 69, passed away Friday, January 5, 2018, surrounded by family and friends. Leland was born May 6, 1948, in Des Moines, Iowa. He was raised on the East side by his...
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Douglas Jay Gandy Of Pulaski, Iowa - Douglas Gandy, age 60, passed away Thursday, January 4, 2018 at the VA Hospital in Des Moines. Doug was born on November 15, 1957 in Des Moines, Iowa. Doug proudly served his...
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Football: remain focused - Wisconsin - Scout
Football: remain focusedJonathan Linder11/23/2005Badgers concentrating on gridiron while in Hawaii; game will feature Pac-10 officialsHONOLULU—While visiting paradise, Wisconsin is focusing on the college football game at hand.
The 24th-ranked Badgers (8-3 overall, 5-3 Big Ten) face host Hawaii (4-6, 4-4 Western Athletic Conference) Friday at 8 p.m. Central Standard Time.. Let's see. Where would you rather be for a week in November? Madison or Honolulu? "We are going to enjoy our time out there and the experience out there," safety Joe Stellmacher said. "But our No. 1 objective is winning the game."
There are plenty of potential distractions on a tropical island, but the Badgers are treating this as a crucial game for their bowl future. "It's going to be tough to balance because it's a break away from the cold weather," tailback Brian Calhoun said. "But people understand that we're out there to win a football game."
Following practice Wednesday, the Badgers were scheduled to visit Pearl Harbor. The team will not fly back to Madison until Sunday evening.
"I think coach (Barry Alvarez) has emphasized we're going to do some great things," linebacker Mark Zalewski said. "He's just saying that we have to take that all in and experience it. It's a great trip…. But any time it comes down to anything football-related it's all business."
A win over Hawaii, coupled with Ohio State securing a BCS at-large bid, would likely earn the Badgers a trip to Orlando for the Capital One Bowl.
Alvarez said he was not sure how much Friday's game would impact his team's postseason destination, but he felt that a nine-win season would make the Badgers attractive to bowl committees. "I would guess that the Capital One Bowl, even if Ohio State was in the BCS, would expect us to win before they would extend an invitation," Alvarez said. Game will feature Pac-10 officials As a result of Hawaii's two contentious home wins over Big Ten schools last season, Wisconsin initially asked the Warriors to accept Big Ten officials for Friday's game. WAC officials customarily referee Hawaii home games. The teams settled on Pac-10 officials for Friday's game. Last season, Northwestern and Michigan State were each called for about twice as much penalty yardage as they were accustomed to; they had a combined 235 yards in penalties marched off. The Spartans had two touchdowns wiped off the board by penalties. The Wildcats and Spartans were highly critical of the officiating after the games, though the MSU game was refereed by a mixed WAC/Big 12 crew. Alvarez admitted Monday that convincing WAC commissioner Karl Benson and Hawaii athletic director Herman Frazier to make a switch was a "very touchy situation."
"You have to be sensitive to Karl. He's the commissioner and what do you tell your officials?" Alvarez said. "Quite frankly, all football coaches are paranoid, and so you worry if you (travel) that far, you have someone else's officials, so on and so forth. It'd be nice if you had neutral officials anytime you had inter-conference games."
Typically, the home conference's officials work non-conference games. Alvarez said, however, that the Badgers try to set up referee swaps when they schedule home-and-home non-conference series. For instance, a Big Ten crew worked the Badgers game at North Carolina this year, and an ACC crew worked the 2003 UNC-UW game in Camp Randall. Share on Facebook Share on TwitterTrending on ScoutNotes: Wheelwright Ready for NebraskaPreview: Huskers on the ReboundScout's Top 5 HS Recruit Highlights - Week 10Notes: Two QBs Providing a Spark at WisconsinUpdated Scout 300 Trend Meter For 2017Share & EmbedInside the Matchup: Nebraska vs Wisconsin Full StoryBadger Nation Top StoriesNotes: Two QBs Providing a Spark at WisconsinIn today's insider notebook, we hear more about the two quarterback system at Wisconsin, the Badgers playing disciplined and more.by Benjamin WorgullBadger NationYesterday at 9:15 PMNotes: Wheelwright Ready for NebraskaIn today's insider notebook, hear from Rob Wheelwright as he prepares for Nebraska and kicker Rafael Gaglianone plans to honor the late Sam Foltz.by Benjamin WorgullBadger NationYesterday at 1:54 PMPreview: Huskers on the ReboundA year after losing seven games by 10 points or less, and six by one possession, No.7 Nebraska comes into this weekend's matchup against No.11 Wisconsin confident it can win the…by Benjamin WorgullBadger NationYesterday at 12:13 PMGame Day Grades - IowaBadgerNation analyzes the game and hands out the grades from Wisconsin's 17-9 win over Iowa at Kinnick Stadium Saturday.by Benjamin WorgullBadger NationYesterday at 7:04 AMInside the Matchup: Nebraska vs WisconsinThe Huskers travel to Madison to face the Badgersby Jonathan KahnScout CFBTuesday at 11:00 AMNotes: Red-Zone Offense MisfiringIn today's insider notebook, Wisconsin talks about what needs to change in the red zone, an update on injuries heading into its matchup with No.7 Nebraska, rotations on the…by Benjamin WorgullBadger NationMonday at 3:39 PMBreaking NewsCichy Done for the SeasonWisconsin's linebacker corps suffered its third major injury of the season, as inside linebacker Jack Cichy is done for the season following a shoulder injury suffered at Iowa…by Benjamin WorgullBadger NationMonday at 10:11 AMBig Ten Recruiting NotebookThe latest on rising prospects, visits, commits and more from around the Big Ten.by Allen TrieuScout FootballYesterday at 9:23 AMParrella says Wisconsin will be challengeNebraska defensive line coach John Parrella talks about the strengths of the Wisconsin offensive line.by Mike WheelerBig Red ReportTuesday at 6:12 PMGerry expects boxing match with WisconsinNebraska senior safety Nate Gerry ahead of the away matchup against Wisconsin.by Mike WheelerBig Red ReportTuesday at 5:33 PMUpdated Scout 300 Trend Meter For 2017The updated Scout 300 Trend Meter for the 2017 class takes a look at which schools are trending for each uncommitted member in the Scout 300.by StaffScout FootballTuesday at 5:40 AMState of the Nation - 10.24.16How does the coaching change at Purdue impact Wisconsin's recruiting? How are UW's in-state commits performing in the state playoffs? All that and more in this week's State of the…by Benjamin WorgullBadger NationMonday at 11:31 AMLoad More

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Andrew Antonopoulos - Semantic Scholar
P K Toutouzas14
M K Kyriakidis14
P N Petropoulakis6
E K Georgiou6
14M K Kyriakidis
14P K Toutouzas
6P N Petropoulakis
6E K Georgiou
5Teresa Seccia
Early atrial arrhythmias in acute myocardial infarction. Role of the sinus node artery.
Michael Kyriakidis, John D. Barbetseas, Andrew Antonopoulos, C G Skouros, Costas Tentolouris, Pavlos K. Toutouzas
We studied atrial arrhythmias during the first 12 h of admission to the hospital in 266 consecutive patients with acute myocardial infarction who subsequently underwent coronary angiography. Ten patients developed atrial fibrillation, one atrial flutter, and one supraventricular tachycardia. Another five developed sinus dysrhythmias. All of the above… (More)
Michael Kyriakidis, Andrew Antonopoulos, E K Georgiou, Ph Santas, Christos Bakirtzis, Pavlos K. Toutouzas
A growing body of data support the beneficial effects of angiotensin-converting enzyme inhibitors in the prevention of cardiac enlargement and improvement of left ventricular function in patients with acute myocardial infarction. However, very little information exists about the direct effect of increased afterload on cardiac performance in these patients… (More)
Sinus node dysfunction in acute inferior myocardial infarction. Role of sinus node artery and clinical course in patients with one-vessel coronary artery disease.
Michael Kyriakidis, Athanasios G Trikas, +5 authors Pavlos K. Toutouzas
To determine the role of the sinus node artery and the clinical course in postmyocardial infarction sinus node dysfunction, 27 patients with acute inferior myocardial infarction and single-vessel coronary artery disease were studied. In 13 patients (group 1) the infarct-related coronary artery was occluded proximally and in 14 (group 2) distally to the site… (More)
Correlation of reciprocal ST-segment depression after acute myocardial infarction with coronary angiographic findings.
Michael Kyriakidis, Andrew Antonopoulos, +4 authors Pavlos K. Toutouzas
We studied 266 consecutive patients with acute myocardial infarction to assess the significance of electrocardiographic "mirror images". Ninety-four (group A) had anterior wall and 132 (group B) had inferior wall infarction. Thirty-one group A patients had stenosis of the right coronary artery greater than 85% in diameter (subgroup A1), and 63 either had a… (More)
The effects of early captopril treatment on left ventricular volumes and function in patients with and without depressed global ejection fraction after acute myocardial infarction.
To determine the effects of captopril on left ventricular volumes and function in patients with and without depressed ventricular function following acute myocardial infarction (AMI) we studied 78 patients with a first Q wave AMI and no clinical evidence of heart failure. All patients underwent radionuclide ventriculography (RVG) on the 4th day after… (More)
Systolic time intervals after phenylephrine administration for early stratification of patients after acute myocardial infarction.
This study was designed to assess the usefulness of the changes in left ventricular (LV) systolic time intervals after phenylephrine administration for detecting high-risk patients soon after acute myocardial infarction by correlation with the angiographic and ventriculographic findings. The procedure was performed in 76 consecutive patients (group I) on… (More)
Scanning electron microscopic observations of Duboscqia penetrans parasitizing root-knot larvae.
Wray Birchfield, Andrew Antonopoulos
Dimitrios K Alexopoulos, Genovefa D. Kolovou, +4 authors Pavlos K. Toutouzas
The significance of angina pectoris in patients with aortic valve disease (AVD) and the need for coronary arteriography before valve replacement are controversial. The history of chest pain and coronary arteriographic findings were reviewed in 333 patients > or = forty years old, with AVD: 142 with aortic stenosis, 87 with mixed AVD and 104 with aortic… (More)
Catastrophic antiphospholipid syndrome presented with severe hypertension, adult respiratory distress syndrome and unilateral adrenal haemorrhagic infarction
Ioannis K. Starakis, Elias E Mazokopakis, Dimitris Siagris, Stamatis N Liossis, Chrysoula Karatza, Andrew Antonopoulos
We are reporting a case of catastrophic antiphospholipid syndrome (CAPS) in an adult female manifested with severe hypertension followed by adrenal haemorrhagic infarction and adult respiratory distress syndrome. Adrenal involvement appears to be exceedingly high in CAPS and adult respiratory distress syndrome (ARDS) is the prevailing pulmonary… (More)
To define coronary angiographic characteristics of patients experiencing early primary ventricular fibrillation (VF) in the acute phase of myocardial infarction we studied 266 consecutive patients without clinical evidence of heart failure. Twenty-six patients (group 1) experienced early (< 12 h from the onset of symptoms of myocardial infarction) primary… (More)

value: This website is an artificial-intelligence backed search engine for academic publications developed at the Allen Institute for AI and publicly released in November 2015. It uses advances in natural language processing to provide summaries for scholarly papers.


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Top 50 coaches: No. 6 Kansas' Bill Self - ESPN
Top 50 coaches: No. 6 Bill SelfBy ESPN.com Stacy Revere/Getty ImagesBill Self coached at Oral Roberts, Tulsa and Illinois before landing at Kansas in 2003.
Editor's note: Over five weeks, we will reveal the top 50 coaches in college basketball as decided by our ESPN Forecast panel. Today we unveil No.6: Kansas' Bill Self. On Monday, we release No. 5.
Have you ever actually read the "Rules of Basket Ball"? Everyone is basically aware of basketball's origin story, the same way everyone can quote at least the first few lines of the Declaration of Independence. But the 13 tenets James Naismith outlined at the YMCA International Training School in Springfield, Massachusetts, in 1891 are fascinating to actually read.
Naismith's distaste for physicality sticks out. It was an explicit part of his mission: His superior at the Springfield YMCA wanted Naismith to create an indoor "athletic distraction" to keep rowdy students in shape, and he wanted to "make it fair for all players, and not too rough." You can hear that voice -- the voice of a gym teacher who needed his students to blow off steam without killing each other -- in the way the rules are written.Ray Carlin/Icon SMISelf reached 300 wins quicker than any other coach in Kansas basketball history.It's often easy to forget that the man who birthed this game unto the world was basically a physical education teacher. It's also easy, given the good doctor's legacy, to forget a more mundane tie: The inventor of the sport was also the first men's basketball coach at Kansas University.
The second coach at Kansas wasn't too bad, either: Forrest Clare "Phog" Allen, whose name adorns Kansas' renowned fieldhouse, was to college basketball what Abraham was to the Old Testament. He played under Naismith. He led the Jayhawks from 1919 to 1956. He coached Adolph Rupp and Dean Smith (and lesser-known Hall of Famers Ralph Miller and Dutch Lonborg). He recruited Wilt Chamberlain. He created the National Association of Basketball Coaches, which eventually created the NCAA tournament.
I write all this because it is an important preface to what follows: By the time his career is over, we might consider Bill Self the best coach in University of Kansas basketball history.
That's a bonkers statement to make, considering Self's KU ancestors. Fortunately, his tenure at the school has been equally bonkers.
The only season in which Self hasn't won or shared the Big 12 title at Kansas was his first one, when his team finished tied for second -- slacker -- and ended the year in the Elite Eight. That was 2003-04. Every year since, Self's Jayhawks have finished first or tied for first in the Big 12.
This is insane in and of itself. The only equivalent we've seen in recent years was Gonzaga's decade-plus run of championships in the West Coast Conference, which is a vastly smaller league with yearly challengers. Gonzaga is an outlier. Kansas is doing it under Self in a major league, against big programs with big budgets, against wave after wave of serious NBA talent. No matter what the situation, no matter the personnel on his roster, Self's teams have finished first.
Here's another fun stat: Since 2006-07, Kansas has been a No. 1 seed five times! Its other seeds: No. 2 (twice) and No. 3 (once). The Jayhawks have averaged 29.5 wins per year under Self! Thursday's coach, Bo Ryan, is often cited as the sport's paragon of consistency. Self is kind of like that ... except his yearly output is everyone else's career year.
How has he done it? For most of his career, according to a time-honored blueprint. Every season, Self would recruit a mix of players ranging from those with obvious NBA futures to those with huge developmental needs, and he would bring them along, year by year, each year losing key pieces but keeping great replacements waiting in the wings. That was how the sport always used to work, back in the days before high school early entry and one-and-done, and for the past decade, no one found more success using that technique than Self.
The 2013-14 season might be the lone departure. All of a sudden, Kansas had a recruiting class that featured two NBA lottery picks. There was also Wayne Selden, another top freshman, and Conner Frankamp, a well-regarded sharpshooter. Self needed to play all of these guys, and the result was his youngest, most inexperienced, most scrutinized roster. To some, the 2013-14 Jayhawks were a disappointment. They won the Big 12 for the 10th straight time anyway.AP Photo/Charlie RiedelSelf's only championship came in 2008, when the Jayhawks defeated Memphis in overtime.That's another of the debates that has occasionally haunted Self. The tournament has not always been kind; Kansas has been upset more times than it has prevailed. What if Mario Chalmers hadn't made that shot in 2008? How would we look at Self then?
Hopefully no differently. The fact of the matter is that basketball is a five-month season, and all you can do is field good teams every year, improve throughout the season and hope things go your way in March. Sometimes they do, sometimes they don't. But even if Self had another title or two, would that be more impressive than 10 straight Big 12 titles? Sample size matters. His players change. He loses waves of personnel. He has teams of veterans, teams of top freshmen, teams with a blend of both. Whatever the situation, for the past decade Self has always been one of the best coaches in the game.
The legend is that when Allen told Naismith he wanted to be a college basketball coach, Naismith told him not to waste his time. "You don't coach basketball, you play it," he said.
Who knows if Self will one day eclipse the architects of KU basketball in the minds of fans. Another decade of conference titles might help. But I do know the inventor was wrong on that one: Basketball can most definitely be coached, and there are few in the world better than the coach at Kansas.
• No. 12: Boeheim » No. 11: Miller » No. 10: Ollie » No. 9: Beilein » No. 8: Marshall »
• No. 7: Ryan »Full Top 50 Coaches ListNo. 50: Tie -- Randy Bennett, Saint Mary's; Scott Drew, Baylor
No. 10: Kevin Ollie, UConn
No. 9: John Beilein, Michigan
No. 8: Gregg Marshall, Wichita State
No. 7: Bo Ryan, Wisconsin
No. 6: Bill Self, KansasCommentsUse a Facebook account to add a comment, subject to Facebook's Terms of Service and Privacy Policy. Your Facebook name, photo & other personal information you make public on Facebook will appear with your comment, and may be used on ESPN's media platforms. Learn more.

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3 bedroom town house for sale in Plots 3 & 4 Wharf Views Riverside Road, Gorleston, NR31
www.rightmove.co.uk/property/72637169
Plots 3 & 4 Wharf Views Riverside Road, Gorleston
ENCLOSED REAR COURTYARD/GARDEN
(NOW OFFERING HELP TO BUY (5% DEPOSIT 75% MORTGAGE REQUIRED)
Delighted to offer three BRAND NEW three storey TWO/THREE BEDROOM mid-terrace TOWN HOUSES (currently under construction) part of a small bespoke development located on the river waterfront in the popular seaside town of Gorleston. The property enjoys ever changing river views from the first floor Juliette balcony.
Velux window White suite, panel bath, vanity sink, w.c and towel radiator.
First floor enclosed garden with access gate leading to the street at the rear of the properties. Ground floor one parking space, access at the rear of the property via covered passage which leads to rear access door into the property and individual store cupboards and bin stores.
EPC RATING B Internal photographs are taken from both plot 1 and plot 5. MARKETING AS THREE BEDROOM AS THE GROUND FLOOR SITTING ROOM IS SUITABLE TO BE USED AS A BEDROOM WITH SHOWER ROOM ON THE SAME FLOOR.
To view this media, please visit the on-line version of this page at www.rightmove.co.uk/new-homes-for-sale/property-72637169.html?premiumA=true
Disclaimer - Property reference 8724057. The information displayed about this property comprises a property advertisement. Rightmove.co.uk makes no warranty as to the accuracy or completeness of the advertisement or any linked or associated information, and Rightmove has no control over the content. This property advertisement does not constitute property particulars. The information is provided and maintained by Homes & Land, Gorleston. Please contact the selling agent or developer directly to obtain any information which may be available under the terms of The Energy Performance of Buildings (Certificates and Inspections) (England and Wales) Regulations 2007 or the Home Report if in relation to a residential property in Scotland.

value: This website is a UK-based company that runs rightmove.co.uk, the UK's largest online real estate portal and property website. It is listed on the London Stock Exchange and is a constituent of the FTSE 100 Index.