The present invention provide methods to improve the treatment of cancer in mammals, including ovarian cancer, where intraperitoneal administration of cytotoxic medical agents or immunoconjugates are utilized. The invention provides means of substantially reducing the level of cytotoxic medical agents or immunoconjugates in the circulating blood. Hence, the organ exposure of circulating cytotoxic agents is minimized using the invention and the invention offers opportunities to use more effective dose treatment regime.

This invention relates to a methods of improving the tumor to non-tumor ratio of cytotoxic targeting agents in the treatment of disseminated carcinomas, in particular ovarian carcinomas, by reducing the concentration of the cytotoxic medical agent in the blood circulation after intraperitoneal administration of a cytotoxic agent and thereby facilitating a higher dosage and thereby a more effective treatment regime without exposing the vital organs to higher toxicity.
Among the various methods presented in this invention, means of extracorporeal removal of the circulating toxic agents is particularly attractive.
Ovarian cancer is the sixth most common cancer among women, excluding non-melanoma skin cancers. The American Cancer Society estimates that about 23,100 new cases of ovarian cancer will be diagnosed in the United States during 2000. Ovarian cancer accounts for 4% of all cancers in women.
Ovarian cancer is also the fifth most common cause of cancer deaths among women, causing more deaths than any other cancer of the female reproductive system. It is estimated that there will be about 14,000 deaths from ovarian cancer in the United States during 2000. About 78% of ovarian cancer patients survive one year after diagnosis and over 50% survive longer than five years after diagnosis. If diagnosed, and treated while the cancer has not spread outside the ovary, the five-year survival rate is 95%. However, only 25% of all ovarian cancers are found at this early stage.
The 5-year survival rate refers to the percent of patients who survive at least 5 years after their cancer is diagnosed. Five-year relative survival rates exclude from the calculations patients dying of other diseases, and are considered to be a more accurate way to describe the prognosis for patients with a particular type and stage of cancer. Of course, 5-year survival rates are based on patients diagnosed and initially treated more than 5 years ago. Improvements in treatment often result in a more favorable outlook for recently diagnosed patients.
There are many types of tumors that can start growing in the ovaries. Some are benign (non-cancerous) and never spread beyond the ovary. These patients can be cured by surgically removing one ovary or the part of an ovary containing the tumor. Other types of ovarian tumors are malignant (cancerous) and may spread to other parts of the body.
In general, ovarian tumors are named according to the kind of cells the tumor started from and whether the tumor is benign or cancerous. There are three main types of ovarian tumors. Epithelial tumors start from the cells that cover the outer surface of the ovary. Cancerous epithelial tumors are called carcinomas. Germ cell tumors start from the cells that produce the eggs (ova). Stromal tumors start from connective tissue cells that hold the ovary together and produce the female hormones, oestrogen and progesterone.
Epithelial ovarian carcinomas (EOC) accounts for 85%-90% of ovarian cancers. The cells of EOC may have several forms that can be recognized under the microscope. In addition to their classification by cell type, EOCs are also given a grade and a stage. The grade is on a scale of 1, 2, or 3. Grade 1 EOC more closely resembles normal tissue and tends to have a better prognosis. Grade 3 EOC less closely resembles normal tissues and usually has a worse outlook. The tumor stage describes how far the tumor has spread from where it started in the ovary.
Effective therapeutic methods for the treatment of ovarian cancer have been subjected to intensive research. Most women suffering from ovarian carcinomas die of loco-regional recurrence and peritoneal dissemination; hence, regional therapy has been the main focus for some time. Experience with intraperitoneal therapy of this tumor using conventional chemotherapy agents (Howel S. et. al. Intraperitoneal cisplatinum-based chemotherapy for ovarian carcinoma, Semin. Oncol. 1991,18 (Suppl 3), 5-10); radioactive colloids (Rosenhein N. B. et. al. Radiocolloids in the treatment of ovarian cancer, Obstet Gynecol Surv 1997, 34, 708-20); immunoadjuvants (Bast R. C. et. al. Intraperitoneal immunotherapy of human ovarian carcinoma with corynebacterium parvum. Cancer Res. 1983, 43, 1395-1401); cytokines (Navoli M. et. al. Intraperitoneal recombinant alpha-2-interferon alternating with cisplatin as salvage therapy for minimal residual-disease ovarian cancer: a phase II study. J. Clin. Oncol 1990, 8(6), 1036-1041) have been reported.
Another area of investigation involves treatment with very high doses of anticancer drugs, and then xe2x80x9crescuingxe2x80x9d the woman from the side effects with infusions of her own bone marrow stem cells or peripheral blood stems cells (immature blood cells that may be taken from the bone marrow or removed from the bloodstream by using a special filtering process). The bone marrow or peripheral blood stem cells are removed before a high dose of chemotherapy is administered and is returned to the woman (reinfused) after the high-dose treatment is complete. In that way, the side effect of suppressed blood cell production is overcome. This is an extremely high-risk, experimental procedure because, for the time, the woman is without her normal supply of blood cells and is very vulnerable to infection.
Targeting biomolecules such as tumor specific monoclonal antibodies are widely used in the treatment of haematological cancer diseases and more recently in the treatment of disseminated solid tumors (Breitz H. B. et. al. Radioimmunotherapy of Solid Tumours, in Radioimmunotherapy of Cancer, eds. P. G. Abrams and A. R. Fritzberg, Marcel Dekker, Inc., New York, 2000, p.265-306).
A number of tumor specific monoclonal antibodies and immunoconjugates, suitable for in vivo diagnosis and treatment of ovarian cancer, have been described in U.S. Pat. No. 4,958,009 (Anti-human ovarian cancer immunotoxins and methods of use thereof), in U.S. Pat. No.5,817,313 (Monoclonal antibodies and conjugates thereof useful for the treatment of cancer), in U.S. Pat. No. 5,804,187 (Modified antibodies with human milk fat globule specificity) and in U.S. Pat. No. 5,650,291 (Monoclonal antibodies against an antigen associated with ovarian cervical and other tumors).
Over the past decade a number of clinical studies using intraperitoneal (i.p.) radioimmunotherapy in ovarian cancer have been reported. Various types of monoclonal antibodies including HMFG-1, HMFG-2, AUA-1 and H 17E2 have been labelled with I-131, Y-90 and Re-186, and injected into the peritoneal cavity through peritoneal dialysis catheter under local anaesthesia in volumes ranging from 1-2 liter of normal saline and a specific activity of 4-8 mCi/mg antibody.
The effective dose for i.p. I-131 labelled antibodies is thought to be 150 mCi and the mean peak radioactivity in serum is at 44 hrs, corresponding to 26% of the total injected dose. Most of the radioactivity given (80%) is found as free iodine in the urine. However, when Y-90 labelled antibodies are used, the mean peak of radioactivity in serum is 23%, and only 8-11% of the injected dose is released in the urine after 72 hrs (Rosenblum M. G. et. al. Clinical pharmacology, metabolism and tissue distribution of Y-90-labelled monoclonal antibody B27.3 after intraperitoneal administration. J. Natl. Cancer Inst. 1991 (83) 1629).
Although, toxic exposure to the peritoneum and its close surrounding is usually well tolerated and is 4-70-fold more advantageous than the i.v. route for targeting of peritoneal tumor sites (Ward, B. G. et. al. Localization of radio iodine conjugated to the monoclonal antibody HMFG-2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration. Cancer Res. 1987 (47) 4719; Ward B. G. et. al. Radiolabelled monoclonal antibodies in oncology. III Radioimmunotherapy. Nucl. Med. Commun. 1991 (12) 333), a high percentage of the injected activity still localizes in normal tissues; the dose-limiting organ being the bone marrow. Myelosuppression arises 4-6 weeks after the initial injection. Grade 3 platelet and granulocyte toxicity (according to the WHO standard) was observed at a total dose of 20 mCi with Y-90 labelled antibody and 160 mCi with I-131 (Stewart J. S. et. al. Intraperitoneal I-131 and Y-90 labelled monoclonal antibodies for ovarian cancer: pharmacokinetics and normal tissue dosiometry. Int. J. Cancer 1988 (3 suppl.), 71; Stewart J. S. et. al. Intraperitoneal yttrium-90 labelled monoclonal antibody in ovarian cancer. J. Clin. Oncol. 1990, (8), 1941; Maraveyas A. et. al. Pharmacokinetics and toxicity of an yttrium-90-CITC-DTPA-HMFG-1 radioimmunoconjugate for intraperitoneal radioimmunotherapy of ovarian cancer. Cancer 1993 (73) 1067), while grade 3 and 4 haematological toxicity was observed at a total dose of 150 mCi with Re-186 (Jacobs A. J. et. al. A phase I trial of a rhenium 186-labeled monoclonal antibody administered intraperitoneally in ovarian cancer carcinoma: toxicity and clinical response. Obstet. Gynecol. 1993 (82) 586).
From the review of the relevant clinical trials, it is clear that i.p. radioimmunotherapy is of benefit mainly to patients with small-volume disease. All studies performed agree that patients with lesions  less than 2 cm have a prolonged disease-free period when compared with historical control group (Hird et. al. Adjuvant therapy of ovarian cancer with radioactive monoclonal antibody. Br. J. Cancer 1993 (82) 586). In the same group of patients, tumor regression has been reported for a number of cases (Epenetos A. A. et. al. Antibody guided irradiation of malignant lesions: three cases illustrating a new method of treatment. Lancet 1984, 1441; Maraveyas A. et. al. Pharmacokinetics and toxicity of an yttrium-90-CITC-DTPA-HMFG-1 radioimmunoconjugate for intraperitoneal radioimmunotherapy of ovarian cancer. Cancer 1993 (73) 1067) as well as decrease in tumor size (Jacobs A. J. et. al. A phase I trial of a rhenium 186-labeled monoclonal antibody administered intraperitoneally in ovarian cancer carcinoma: toxicity and clinical response. Obstet. Gynecol. 1993 (82) 586).
However, the results are rather poor in patients with nodules  greater than 2 cm in diameter subjected to radioactive doses at, or close to, the maximum tolerated dose, since too little of the radioactive antibodies are penetrating the tumorous tissue and the high-energy radiation reaches the limit of its distant killing effect (Ward B. et. al. The treatment of intraperitoneal malignant disease with monoclonal antibody guided 131-I radiotherapy. Br. J. Cancer 1988 (58) 658). This group of patients number more than 50% of patients in need of treatment. Thus, the dose necessary to reach an effective therapy in this group of patients is hampered by the accumulation of radioactivity in the blood circulation, leading to toxicity of normal organs, notably the bone marrow.
Other carcinomas where intraperitoneal administration of cytotoxic medical agent could be applicable, either alone, or in combination with intravenous administration, includes, but is not limited to, colon and/or rectal cancer.
Most medical agents, and in particular larger molecules, administered into the peritoneal cavity are transported to the blood mainly through the lymphatic system, provided that the peritoneum remains intact. If these molecules are toxic to cells they may do considerable damage to body tissues outside the peritoneal cavity such as kidney, liver, lung and bone marrow, and may even be fatal. It is desirable to remove such materials from the blood as quickly as possible. Although the body has natural clearance mechanisms to remove exogenous molecules from the blood circulation, these systems are rather slow for in particular immunoglobulins; leading to a high toxic exposure to the clearing organs such as liver and/or kidney.
Various means to clear the blood from cytotoxic targeting biomolecules (e.g. therapeutic or diagnostic monoclonal antibodies) after i.v. administration have been reported (see review article by Schriber, G. J. and Kerr, D. E., Current Medical Chemistry, 1995, Vol. 2, pp 616-629).
In the so-called avidin chase modality, avidin or streptavidin is administered systemically after administration of the therapeutic or diagnostic antibody to which biotin has been attached, at a time when a sufficient amount of the antibody has been accumulated in the tumor. Avidin or streptavidin will associate with the antibodies and the so formed immunocomplex will clear from the blood circulation via the reticuloendothelial system (RES) and be cleared from the patient via the liver. These procedures will improve the clearance of biotinylated cytotoxic antibodies. An alternative approach to the same end, is the use of anti-idiotypic antibodies. However, all these methods rely on the liver or kidney for blood clearance and thereby expose either or both of these vital organs as well as the urinary bladder to high dose of cytotoxicity. Another major drawback of the methods is the immunogenicity of these agents, particularly the streptavidin, which prevent repetitive treatments once the immune response has been developed.
Extracorporeal techniques for blood clearance are widely used in kidney dialysis, where toxic materials build up in the blood due to a lack of kidney function. Other medical applications where an extracorporeal device can be used include: removal of radioactive materials; removal of toxic levels of metals; removal of toxins produced from bacteria or viruses; removal of toxic levels of drugs, and removal of whole cells (e.g. cancerous cells, specific haematopoietic cellsxe2x80x94e.g. B, T, or NK cells) or removal of bacteria and viruses.
In a preferred embodiment of the invention, a cytotoxic targeting biomolecule (e.g. immunoconjugate) used for therapy of human ovarian cancer is removed from the blood to improve its ratio of target-to-non-target concentration. An improved target-to-non-target ratio provides a better therapeutic index. Specific tissue or organ localization of a biomolecule is a very important factor in its effective application. Lack of specific tissue localization is of particular importance in the treatment with cytotoxic biomolecules, where the desired effect is to kill certain types of cells such as in the treatment of cancer. In order to enhance the specificity, tumor specific monoclonal antibodies are used as a carrier (immunoconjugates) of various cytotoxic moieties, such as, but not limited to, radionuclides, chemotherapy drugs, synthetic or naturally occurring toxins, immunosuppressive agents, immunostimulating agents, and enzymes used in prodrug protocols (Meyer et al., Bioconjugate Chem. 6, 440-446; 1995; Houba et al., Bioconjugate Chem. 7, 606-611, 1996; Blakey et al., Cancer Res. 56, 3287-3292, 1996).
Although tumor-specific immunoconjugates are selectively bound to tumor cells, an initial high concentration of the cell-toxic immunoconjugate in the peritoneal fluid is necessary to reach a sufficiently high concentration in the target tissue. While required for optimal therapy of the cancer, the high concentration of cytotoxic material in the peritoneal fluid will gradually increase the level of the cell toxic material in the blood and other non-tumor tissues, in most cases leading to tissue damage and/or lesion formation in sensitive and vital tissues like the bone marrow. Although, bone marrow rescue is sometimes used to circumvent these potentially lethal effects, such rescue is both extremely costly and poses high risk for the patient.
Even in cases where the bone marrow rescue is effective, other sensitive organs like the liver, kidney, spleen, lung, etc. can be irreparably damaged. The most effective method for preventing tissue and bone marrow damage from toxic materials in blood is to dramatically decrease the amount of that toxic material in the blood. Of course, this must be accomplished in a manner that retains the therapeutic level of toxic material in the tissue being treated (e.g. tumor). Direct transport from the peritoneal fluid to the blood circulation is not considered to be of major significance for most cytotoxic medical agents compared to the lymphatic transportation route. Hence, the concentration of cytotoxic medical agents in the peritoneal fluid is only to a small extent dependent on the concentration of the same medical agent the blood circulation.
Various methods have been proposed to rapidly clear radiolabeled antibodies from blood circulation after the tumor has accumulated a sufficient quantity of immunoconjugate to obtain a diagnosis or therapy. Some of the methods employed involve enhancement of the body""s own clearing mechanism through the formation of immune complexes. Enhanced blood clearance of radiolabeled antibodies can be obtained by using molecules that bind to the therapeutic antibody, such as other monoclonal antibodies directed towards the therapeutic antibody (Klibanov et. al., J. Nucl. Med. 29, 1951-1956, 19888; Marshall et al. Br. J. Cancer 69, 502-507, 1994; Sharkey et al. Bioconjugate Chem. 8, 595-604, 1997), avidin/streptavidin (Sinitsyn et al., J. Nucl. Med. 30, 66-69,1989; Marshall et. al., Br. J. Cancer, 71, 18-24, 1995), or glycosyl containing compounds which are removed by receptors on liver cells (Ashwell and Morell, Adv. Enzymol. 41, 99-128, 1974). Still other methods involve removing the circulating immunoconjugates through extracorporeal methods (see review article by Schriber, G. J. and Kerr, D. E., Current Medical Chemistry, 1995, Vol. 2, pp 616-629).
The extracorporeal techniques used to clear a medical agent from blood circulation are particularly attractive because the toxic material is rapidly removed from the body. Application of these methods in the context of immunotherapy have been previously described (Henry Chemical Abstract, 1991, Vol.18, pp. 565; Hofheinze D et al., Proc. Am. Assoc. Cancer. Res. 1987 Vol. 28, pp 391; Lear J K, et al. Radiology 1991, Vol. 179, pp. 509-512; Johnson T. K. et. al. Antibody Immunoconj. Radiopharm. 1991, Vol. 4, pp. 509; Dienhart D. G., et al. Antibody Immunoconj. Radiopharm. 1991, Vol. 7, pp. 225; DeNardo G. L. et al. J. Nucl. Med. 1993, Vol. 34, pp1020-1027; DeNardo S. J. et. al. J. Nucl. Med. 1992, Vol. 33, pp. 862-863; DeNardo G. L. J. Nucl. Med. 1992, Vol. 33, pp. 863-864; and U.S. Pat. No. 5,474, 772 (Method of treatment with medical agents.).
To make the blood clearance more efficient and to enable processing of whole blood, rather than blood plasma as the above methods refer to, the medical agents (e.g. tumor specific monoclonal antibody carrying cell killing agents or radionuclides for tumor localization) have been biotinylated and cleared by an avidin-based adsorbent on a column matrix. A number of publications provide data showing that this technique is both efficient and practical for the clearance of biotinylated and radionuclide labelled tumor specific antibodies (Norrgren K, et. al. Antibody Immunoconj. Radiopharm. 1991, Vol. 4, pp 54; Norrgren K, et .al. J. Nucl. Med. 1993, Vol. 34, pp. 448-454; Garkavij M, et. al. Acta Oncologica 1996, Vol. 53, pp.309-312; Garkavij M, et. al. J. Nucl Med. 1997, Vol.38, pp.895-901. These techniques are also described in EP0 567 514 (A method and a system for enhanced in vivo clearance of diagnostic and/or therapeutic agents by extracorporeal depletion, and the use of said agents for said purpose). A further development of this method where simultaneous labelling of biotin and radionuclides is described in a patent application by Nilson et al., PCT/SE92/0020 (from which priority is claimed), A Method and a System for Enhanced In Vivo Clearance of Diagnostic and/or Therapeutic Agents by Extracorporeal Depletion, and the Use of said Agents for Said Purpose; and an application by S. Wilbur and B. E. B. Sandberg PCT/SE98/01345, Trifunctional reagent for the conjugation to a biomolecule .
Apart from the prolonged circulation time leading to undesired exposure of toxic immunoconjugate to healthy tissue, inadequate tumor tissue penetration and non-specific organ retention and metabolism contribute to a low therapeutic index ratio. Due to these problems, multi-step antibody-based radionuclide delivery approaches have been extensively investigated. The basic concept involves first the injection of a lesion-specific targeting moiety, which apart from binding specifically to the lesion also has the feature of binding to a subsequently injected radioactive diagnostic agent or a therapeutic agent. By separating these two events one can allow the slow tissue penetrating non-radioactive/non-cytotoxic antibody sufficient time to accumulate in the tumor mass, while the agent carrying the radionuclide/cytotoxin could be selected for more rapid tissue penetration. However, a prerequisite is that the former (and preferably also the later) can be cleared rapidly from the blood circulation.
The so called two and three-step approaches have recently been reviewed in the context of intraperitoneal administration in ovarian cancer therapy (Syrigos K. N. and Epenetos A. A. (2000) Intraperitoneal Radioimmunotherapy of Ovarian Cancer in Radioimmunotherapy of Cancer, eds. P. G. Abrams and A. R. Fritzberg, Marcel Dekker, Inc., New York, p. 315-316).
The present invention relates to improvements in the diagnosis and treatment of peritoneal cancers, including ovarian cancer. The method is based on reducing the level of cytotoxic medical agents or toxic immunoconjugates from the blood circulation, after intraperitoneal injection of these compounds. By depleting the circulating cytotoxic medical agent or immunoconjugate, it is possible both to decrease the toxic side effect on other organs and at the same time increase the therapeutic dose in a single administration or through administration of multiple doses, which results in an increased penetration of the tumor tissue by the cytotoxic medical agent or immunoconjugate.
Thus, in one embodiment, the subject invention comprises a method for improving the treatment of intraperitoneal cancers in mammals comprising: (a) administering a biomolecule intraperitoneally to said mammal; and (b) substantially reducing the level of said biomolecule or a cytotoxic fragment thereof in the blood circulation at suitable time intervals, whereby side effects associated with circulating biomolecule or cytotoxic fragment are reduced. Preferably, the reduction of biomolecule or cytotoxic fragment in the circulation is achieved by passing the blood or a component thereof through an extracorporeal adsorption device. The blood component may be serum or plasma. The extracorporeal device comprises a solid support with a receptor bound thereto; and the biomolecule or cytotoxic fragment is conjugated to an affinity ligand with a high affinity to the receptor. Alternatively, the biomolecule or cytotoxic fragment has a high affinity to the receptor.
The biomolecule can be a cytotoxic medical agent; a cytotoxic medical agent conjugated to a targeting agent; and a targeting agent conjugated to a cytotoxic moiety which is selected from the group consisting of a radionuclide, a chemotherapy drug, a synthetic or naturally occurring toxin, an immunosuppressive, an immunostimulant, and a prodrug activating enzyme. If the biomolecule is the cytotoxic medical agent conjugated to a targeting agent, it is preferred that the affinity ligand be directly covalently bound to the cytotoxic medical agent. If the biomolecule is the targeting agent conjugated to the cytotoxic moiety, it is preferred that the affinity ligand be directly covalently or coordinately bound to the radionuclide or directly covalently bound to the chemotherapy drug, the synthetic or naturally occurring toxin, the immunosuppressive, the immunostimulant, or the prodrug activating enzyme.
The cytotoxic fragment of the biomolecule is a molecule comprising a radionuclide or a toxic metabolite or structure derived from the cytotoxic medical agent, the chemotherapy drug, the synthetic or naturally occurring toxin, the immunosuppressant, the immunostimulant or the prodrug activating enzyme.
In a preferred embodiment, the invention comprises a method for improving the treatment of intraperitoneal cancers in mammals comprising: (a) administering a conjugate of a biomolecule and an affinity ligand intraperitoneally to the mammal; and (b) substantially reducing the level of said biomolecule or cytotoxic fragment thereof in the blood circulation by passing at suitable time intervals the blood or a component thereof through an extracorporeal device comprising a solid support having a receptor bound thereto, the affinity ligand having a high affinity to the receptor, whereby the level of biomolecule or cytotoxic fragment in the circulation is reduced.
The invention also comprises a system for substantially reducing the level of a biomolecule or cytotoxic fragment thereof in a mammal""s blood or component thereof, wherein the biomolecule has been administered intraperitoneally, said system comprising an extracorporeal device having immobilized receptors therein, through which the mammal""s blood or a component thereof is passed, whereby the receptors, which have a high affinity for the biomolecule or the cytotoxic fragment, or for an affinity ligand bound to the biomolecule or the cytotoxic fragment, immobilize the biomolecule or the cytotoxic fragment in the device; means for transporting the blood or blood component to the extracorporeal device; and means for delivering treated blood or blood component from the extracorporeal device to the mammal.
The subject invention further comprises a method for improving the imaging of peritoneal cancers in mammals comprising: (a) administering a conjugate of a radionuclide and a targeting agent intraperitoneally to said mammal, wherein said targeting agent has a high affinity for the cancer; and (b) substantially reducing the level of radionuclide in the blood circulation at suitable time intervals, whereby side effects associated with circulating radionuclide are reduced or whereby imaging contrast is improved. Preferably, the reduction of radionuclide in the circulation is achieved by passing the blood or a component thereof through an extracorporeal adsorption device. The extracorporeal device comprises a solid support with a receptor bound thereto, and the conjugate of radionuclide and targeting agent, or a cytotoxic fragment thereof, is further conjugated to an affinity ligand with a high affinity to the receptor. Alternatively, the receptors in the extracorporeal may have a high affinity to the targeting agent. In a preferred embodiment, a radionuclide is directly covalently or coordinately bound to the affinity ligand, which is directly covalently bound to the targeting agent.
The invention can be illustrated with the simulation exemplified in Example 1. As is explained in Example 1, clinical data from Maraveyas, A. et al. (Cancer 73:1067-1075, 1994) relating to intraperitoneal administration of 90Y-HMFG-1 to patients with ovarian cancer were utilized in the simulation. These data were utilized to simulate the effects of two extracorporeal adsorptions with Mitradep(copyright) (a blood filter having avidin immobilized to agarose particles) conducted at various time after administration of the antibody conjugate. Each adsorption is assumed to remove 90 per cent of the circulating conjugate. It is also assumed that the rate of transport of conjugate from the intraperitoneal volume to blood or the biological half-life of the conjugate in blood is not influenced by the extracorporeal adsorptions. The results illustrated in FIG. 1 illustrate how treatment of the blood at selected time intervals after administration can significantly or substantially reduce the level of biomolecule in the blood, thereby substantially reducing side effects associated with the circulating biomolecule and enhancing the target to non-target ratio for the biomolecule. This improved ratio can result in decreased side effects and/or improved contrast for imaging.
Although the present invention is described for application to human ovarian carcinoma it is also applicable to other types of human cancer diseases where intraperitoneal administration is deemed preferable. The subject procedure is also suitable for the treatment of other mammalian species. The clearance of the biomolecule from the blood is achieved by passing the patient""s whole blood through a device that specifically adsorbs the biomolecule. In the most preferred application, the biomolecule is labelled with biotin and the blood clearance is achieved by passing the blood on-line through a device coated with avidin or streptavidin. Such a device is described in EP0 567514 and exhibits the proper characteristics of the matrix and means of immobilizing the biotin-binding entity for processing of whole blood and obtaining excellent clearance in a reasonable time period. The biocompatibility of an agarose matrix containing immobilized avidin for clinical use has been reported (Bosch, T. et al., Ex Vivo Biocompatibility of Avidin-Agarose: A New Device for Direct Adsorption of Biotinylated Antibodies from Human Whole Blood. Artificial Organs, 2000). It should be stressed that all extracorporeal applications where the patient""s whole blood is processed would also be applicable for the processing of human plasma, although such a system would be both more cumbersome and less efficient.
All references cited herein are incorporated by reference in their entireties.


A diaper storage and dispensing device and method is disclosed including a housing having an interior within which a stack of diapers is stored. The diapers are preferably stacked on top of a movable platform. The housing includes an access aperture through which the device can be stocked with diapers. The movable platform is preferably under tension in order to press the diapers upward. A dispensing opening is located toward the top of the device. The top diaper is aligned with the dispensing opening, and a diaper displacement mechanism operates to advance a single diaper at least partially out through the dispensing opening. The displacement mechanism is operated by a user pressing on a lever such as a foot pedal. After the diaper is removed, the next diaper in the stack is aligned with the displacement mechanism and the dispensing opening.

The present invention relates to diaper dispensing devices, and more specifically to a diaper storage and dispensing device for selectively dispensing individual diapers, and a method for making the same.
Infants and toddlers must be diapered multiple times a day. Due to the numerous burdens on the caretaker of children, it is important to provide diapers in the most convenient manner available.
Various prior art devices exist to store diapers. However, such devices do not provide sufficient convenience to the user.
For example, U.S. Pat. No. 5,678,727 issued to Rice discloses a diaper dispenser apparatus. The Rice apparatus provides a storage means for diapers, and an opening for manually pulling diapers out of the device. Such a device is insufficient because manually separating and pulling the diaper out of the device is a cumbersome task.
Other prior art devices fail to adequately address these concerns. Therefore, it would b e advantageous to provide a diaper storage and dispensing device which provides an easier means for the user to access and remove a diaper when needed.
In view of the deficiencies described above, it is an object of the present invention to provide a diaper storage and dispensing device which will conveniently dispense diapers upon the need of the user.
In accordance with the above objectives, the present invention is a diaper storage and dispensing device. The device includes a housing which stands substantially vertically. The housing has an interior within which a stack of diapers is stored. The diapers are preferably stacked on top of a movable platform. The housing includes an access aperture through which the device can be stocked with diapers.
The movable platform is preferably under tension in order to press the diapers upward. A dispensing opening is located toward the top of the device. The top diaper is aligned with the dispensing opening, and a diaper displacement mechanism operates to advance a single diaper at least partially out through the dispensing opening.
The displacement mechanism is operated by a user pressing on a lever such as a foot pedal. After the diaper is removed, the next diaper in the stack is aligned with the displacement mechanism and the dispensing opening.
A method for manufacturing the device of the present invention by providing the various components described in detail below is also disclosed.
Other features and advantages of the invention will be apparent from the following detailed description taken in conjunction with the following drawings.


A method of improving health in a canine includes administering to the canine a nutritional supplement comprising an amino acid secretagogue composition, which stimulates the pituitary gland of the canines to produce growth hormone. The nutritional supplement may be administered orally. The nutritional supplement may comprise L-arginine hydrochloride, Oxo-proline, L-lysine hydrochloride, and cysteine. When desired, the nutritional supplement may consist essentially of L-arginine hydrochloride, Oxo-proline, L-lysine hydrochloride, N-acetyl-L-cysteine, L-glutamine, and schizonepeta powder.

Growth hormone is an anabolic hormone capable of promoting linear growth, weight gain and whole body nitrogen retention in animals. Growth hormone is produced in somatotroph cells of the anterior pituitary gland of animals and secreted throughout life. It is mainly controlled in the brain by two hypothalamic peptides: growth hormone releasing hormone (GHRH), which stimulates its secretion and synthesis; and somatostatin, which inhibits them. In human beings and other mammals, regulated expression of the growth hormone pathway is considered essential for optimal linear growth, as well as homeostasis of carbohydrate, protein and fat metabolism.
As canines age, their growth hormone levels decrease considerably resulting in a loss of skeletal muscle mass, osteoporosis, increased fat deposition, decreased lean body mass, and other disorders. Studies in human beings and other mammals have demonstrated that the recombinant growth hormone therapy may address the reduction of growth hormone. However, the recombinant growth hormone therapy for canines is limited and has proved to be inefficient.
U.S. Pat. No. 7,361,642, issued on Apr. 22, 2008 to Draghia-Akli, discloses a method for increasing growth hormone in canines. A canine-specific growth hormone releasing hormone (dGHRH) or a nucleic acid molecule that encodes the dGHRH is administered to canines to increase the level of growth hormone secretion. The canines treated with specific growth hormone releasing hormone show increased insulin-like growth factor I, enhanced red blood cells production and hemoglobin concentration, and improved protein metabolism.
Journal of Orthopedic Research 15:519-527 (1997) discloses that a growth hormone secretagogue, MK-0677, elevates levels of serum insulin-like growth factor-I in canines, which in turn increases the size and strength of the quadriceps muscle in canines during remobilization.
U.S. Publication No. 2008/0119819, published on May 22, 2008 to Hojby, discloses that an administration of growth hormone enhances bone growth factors and fracture healing in canines.
It has also been reported that for adult canines of both sexes, exogenous growth hormone induces a marked increase in new bone formation. (Calcified Tissue Research 10(1):1-13 (1972)).
Other studies have shown that in the canines that were given growth hormone, the quantity of protein in the blood plasma is increased, and the plasma protein pattern is altered. (Endocrinology 53: 134-162 (1953)). Additionally, it is known that growth hormone treatment improves protein metabolism in canines.

This patent is subject to a terminal disclaimer.


A thermosetting composition with a glass transition temperature of at least 100xc2x0 C. comprises at least one epoxy resin formed from at least one polyepoxide containing at least two epoxy groups in its molecule and at least one aromatic polyamine containing at least two primary amino groups in its molecule, at least one alkanoyl substituent containing 1 to 12 carbon atoms located in the position alpha to one of the amino groups. The molar ratio of the amine to the epoxide is such that each amine group corresponds to 1.6 to 2.6 epoxy groups. The composition also includes a flow controller. The composition can be used as a protective coating for any metallic or non metallic surface. The invention also concerns a flexible deployable preform comprising the composition.

The present invention concerns a flexible preform which is radially deployable to form a tubular structure which is hardenable following deployment after positioning in a well or conduit to mould to its shape, to constitute a casing which is usually substantially cylindrical.
Preforms are known with walls of flexible material which can be collapsed on itself to give a radial dimension which is much smaller than the diameter of the well or conduit to be cased in the event of local repair of a well or casing. The preform is introduced into the well or conduit in its collapsed state and once it is in the desired position, it is deployed by radial outward deformation, for example by introducing an inflating fluid such as a gas or liquid inside the preform The applied pressure causes it to mould to the shape of the well or conduit. Such preforms normally comprise a thermosetting resin. In general, the resin forms part of the constituting wall of the preform and is very often introduced by impregnating the fibres forming the wall. Hardening the resin by thermosetting may be brought about by the temperature in the well, but normally it is caused either by introducing a hot fluid inside the preform or by a Joule effect using suitable electrical resistors located in the preform, for example electric wires forming part of the frame of the preform wall, impregnated with thermosetting resin. The heat released by an exothermic reaction which is initiated inside the preform can also be used, usually by bringing the reactants into contact at the desired time.
The preform of the present invention can be positioned and anchored without the need for cement. Within the context of the present invention, the term xe2x80x9cflexible preformxe2x80x9d means any assembly preferably having an integrated heating system which can hold a thermosetting resin in a medium confined between outer and inner skins of elastic material. Preforms of this type are described, for example, in French patent FR-A-2 722 239, and International patents WO-A-94/21887, WO-A-94/18180 and WO-A-94/25655. The contents of these patents are hereby incorporated by reference and are considered to form an integral part of the present description.
Such preforms must comprise a thermosetting resin having particular characteristics. The resin used must confer superior mechanical properties on the preform, in particular when used in wells, especially in oil wells, they must have high resistance to hydrothermal and chemical ageing, they must have as small as possible a water take-up and the highest possible latency, to allow storage and transport of the preform before it is put in position without the polymerisation reaction starting or having advanced too far.
The present invention also concerns thermosetting compositions with improved latency, with a low water take-up, having a glass transition temperature of at least 100xc2x0 C., preferably at least 120xc2x0 C. and more preferably at least 140xc2x0 C., comprising at least one epoxy resin formed from at least one polyepoxide containing at least two epoxy groups in its molecule and at least one aromatic polyamine containing at least two primary amino groups in its molecule and at least one alkanoyl substituent containing 1 to 12 carbon atoms located in the position alpha to one of the amino groups, the molar ratio of the amine to the epoxide being such that each amino group corresponds to 1.6 to 2.6 epoxy groups, the thermosetting compositions of the invention further comprising a flow controller.
The present invention also concerns the use of these compositions for the production of pre-impregnates with high latency in processes demanding intermediate steps of several hours at 80xc2x0 C. and the use of these compositions as protective coatings in conduits for fluids (liquid, gas or a mixture of liquid and gas), in particular transport conduits for liquid and/or gaseous hydrocarbons. These coatings can be applied to the inside and also to the outside of the conduits. The invention further concerns the use of these compositions as protective coatings for storage facilities. In general terms, the invention concerns the use of these compositions as a protective coating for any metallic or non metallic surface which can come into contact with agents which cause the degradation of a material or the surface of a material when they come into contact with the surface of the material. More precisely, this is the case for any surface which comes into contact with a corrosive atmosphere or with an adsorbable or absorbable product causing swelling of the material. In the case of conduits or storage facilities for hydrocarbons, these coatings, which have a very low water adsorption capacity, can prevent corrosion by water by preventing direct contact between the material and water or humidity contained in the product in contact with the material, which can be earth in the case of buried conduits or facilities, air in the case of above-ground conduits or facilities, or the moisture contained in hydrocarbons. The scope of the invention also includes the use of these compositions in the micro-electronics field and in the electromechanical field, two fields in which a very low water adsorption capacity is an important factor.
The choice of aromatic polyamines used in the present invention is guided in particular by the fact that it is desirable to have access to aromatic polyamines with low reactivity and low solubility at a temperature of less than about 90xc2x0 C., occasionally less than about 40xc2x0 C., in the epoxy resins used. The choice is also influenced by the fact that these aromatic polyamines must preferably result in good resistance to hydrolysis by secondary and tertiary amine moieties which it generates by reaction on the epoxide ring. It must also result in good temperature resistance properties.
In its widest form, then, the present invention concerns a radially deployable flexible preform which forms a tubular structure which is hardenable following deployment after positioning in a well or a conduit to mould to its shape, characterized in that it comprises at least one epoxy resin formed from at least one polyepoxide containing at least two epoxy groups in its molecule, and at least one aromatic polyamine containing at least two primary amino groups in its molecule and at least one alkanoyl substituent containing 1 to 12 carbon atoms located in the position alpha to one of the amino groups, the molar ratio of the amine to the epoxide being such that each amino group corresponds to 1.6 to 2.6 epoxy groups.
Processes using aromatic polyamines as hardeners for certain epoxy resins are known in the industry, such as the various types of ARALDITE(copyright), EPIKOTE(copyright) resins, EPON(copyright) resins, the resin obtained from the diglycidylether of bis-phenol-F (hereinafter abbreviated to DGEBF) and, in particular, the resin obtained from the diglycidylether of bis-phenol-A (hereinafter abbreviated to DGEBA). In these processes, express recommendations are made that the amine be dissolved before impregnation into the reinforcing fibre, for example glass fibre, carbon fibre, ceramic fibre or a natural or synthetic fibre. The skilled person is aware that practically any aromatic polyamine can be used as an epoxy resin hardener. Selection of a limited number of polyamines which could produce the required properties for the preforms of the invention would thus not be obvious.
The epoxy resin can be selected from the group formed by the commercially available resins cited above, the diglycidylether of bis-phenol-A or bis-phenol-F, bis-phenol formol resin, phenol-novolac resin, cycloaliphatic resins, tri- or tetra-functional resins, resins formed from triglycidylether-isocyanurate and/or triglycidylether-cyanurate and/or triglycidyl-cyanurate and/or triglycidyl-isocyanurate, or mixtures of at least two of these resins.
The epoxy resins obtained from the epoxy resins cited in U.S. patent U.S. Pat. No. 4,921,047 can also be used within the context of the present invention. The content of this patent is hereby incorporated by reference and is considered to form an integral part of the present description.
The epoxy resin selected usually has a dynamic viscosity of about 0.04 to about 50 Paxc2x7s at about 25xc2x0 C.
Of the amines which could achieve the fixed technical specifications for the preforms, aromatic amines containing a single aromatic ring could be considered. However, it is preferable in the present invention to use aromatic amines containing at least two aromatic rings. In this case, these amines often contain two aromatic rings connected together via a bivalent substituted or unsubstituted hydrocarbon residue containing 1 to 18 carbon atoms. These two aromatic rings are either connected by a bivalent alkoyl group or are connected together via a bivalent substituted or unsubstituted hydrocarbon residue containing 6 to 18 carbon atoms and containing an aromatic ring.
The amine can also comprise at least one substituent selected from the group formed by fluorine, iodine, bromine and chlorine. It preferably contains at least two alkoyl substituents, each being alpha either side of an amino group.
When the two aromatic rings are connected by a bivalent alkoyl residue, the residue is preferably an unsubstituted methylidene group, or a methylidene group substituted by at least one radical selected from alkoyl radicals and halogenoalkoyl radicals containing 1 to 3 carbon atoms. As an example, the alkoyl residue can be selected from the group formed by the methylidene group, the isopropylidene group, halogenoisopropylidene groups, and the hexafluoroisopropylidene group. In this case, the amine is preferably selected from the group formed by:
4,4xe2x80x2-methylene-bis(2,6-dimethylaniline), or M-DMA;
4,4xe2x80x2-methylene-bis(2-isopropyl-6-methylaniline), or M-MIPA;
4,4xe2x80x2-methylene-bis(2,6-diethylaniline), or M-DEA;
4,4xe2x80x2-methylene-bis(2,6-diisopropylaniline), or M-DIPA; and
4,4xe2x80x2-methylene-bis(3-chloro-2,6-diethylaniline), or M-CDEA.
Of these amines, 4,4xe2x80x2-methylene-bis(2,6-diethylaniline) and 4,4xe2x80x2-methylene-bis(3-chloro-2,6-diethylaniline) are of particular interest.
When the amine contains two aromatic rings which are connected together via a bivalent substituted or unsubstituted hydrocarbon residue containing 6 to 18 carbon atoms and containing an aromatic ring, it is preferably selected from the group formed by:
4,4xe2x80x2-(phenylene-diisopropyl)-bis(2,6-dimethylaniline);
4,4xe2x80x2-(phenylene-diisopropyl)-bis(2,6-diethylaniline);
4,4xe2x80x2-(phenylene-diisopropyl)-bis(2,6-dipropylaniline);
4,4xe2x80x2-(phenylene-diisopropyl)-bis(2,6-diisopropylaniline);
4,4xe2x80x2-(phenylene-diisopropyl)-bis(2,6-dimethyl-3-chloroaniline);
4,4xe2x80x2-(phenylene-diisopropyl)-bis(2,6-diethyl-3-chloroaniline);
4,4xe2x80x2-(phenylene-diisopropyl)-bis(2,6-dipropyl-3-chloroaniline);
4,4xe2x80x2-(phenylene-diisopropyl)-bis(2,6-diisopropyl-3-chloroaniline);
3,3xe2x80x2-(phenylene-diisopropyl)-bis(2,6-dimethylaniline);
3,3xe2x80x2-(phenylene-diisopropyl)-bis(2,6-diethylaniline);
3,3xe2x80x2-(phenylene-diisopropyl)-bis(2,6-dipropylaniline);
3,3xe2x80x2-(phenylene-diisopropyl)-bis(2,6-dimethyl-3-chloroaniline);
3,3xe2x80x2-(phenylene-diisopropyl)-bis(2,6-diethyl-3-chloroaniline);
3,3xe2x80x2-(phenylene-diisopropyl)-bis(2,6-dipropyl-3-chloroaniline);
3,3xe2x80x2-(phenylene-diisopropyl)-bis(2,6-diisopropylaniline); and
3,3xe2x80x2-(phenylene-diisopropyl)-bis(2,6-diisopropyl-3-chloroaniline)
In a particular embodiment of the invention, the preform comprises at least one epoxy resin formed from at least one polyepoxide containing at least two epoxy groups in its molecule, and at least two aromatic polyamines.
The compositions of the present invention must satisfy the following conditions of use in order to be able to be used for the production of flexible preforms of the present invention:
They must be capable of providing a pot life, either stored or on the reinforcing fibres, for example glass fibres or their equivalent, of 20 days or more, normally about 30 days to about 4 months, more specifically about 30 days to about 2 months and at an average storage temperature of 25xc2x0 C. or less, normally about 0xc2x0 C. to about 15xc2x0 C. and more preferably about 0xc2x0 C. to about 5xc2x0 C.;
They must be capable of providing a residual latency of at least 3 hours, preferably at least 6 hours, after pot storage or storage on a support, at a temperature of about 70xc2x0 C. to about 90xc2x0 C., normally at least 8 hours at a temperature of about 80xc2x0 C. The residual latency is more preferably at least 5 hours at 100xc2x0 C. (or even 120xc2x0 C.), preferably at least 7 hours at that temperature;
They must be capable of providing a residual latency of at least 8 hours, preferably at least 10 hours and more preferably at least 11 hours, at a temperature of about 70xc2x0 C. to about 90xc2x0 C., more preferably about 80xc2x0 C., after pot storage or storage on a support for a period of at least 90 days, normally about 90 days to about 6 months and more preferably about 90 days to about 4 months at a temperature of xe2x88x9218xc2x0 C. or less, normally about xe2x88x9230xc2x0 C. to about xe2x88x9218xc2x0 C. and more preferably about xe2x88x9225xc2x0 C. to about xe2x88x9218xc2x0 C.;
They must be capable of being deposited on fibrous supports such as glass fibres, carbon fibres, KEVLAR(copyright) fibres, on metal fibres or wires, on ceramic fibres or on natural or synthetic fibres in conventional fashion, whether manually or mechanically. This means that compositions having a relatively low dynamic viscosity, to allow good impregnation of the fibres forming the walls of the preform, must be selected. This dynamic viscosity is at the temperature used for impregnating the fibres, often less than 2500 mPaxc2x7s (millipascals second) and normally about 300 to about 2500 mPaxc2x7s; it can be of the order of 1500 mPaxc2x7s;
It must satisfy hygiene and safety regulations;
It must have a polymerisation temperature which is compatible with the heat resistance of the polymers constituting the walls of the preform, i.e., normally a polymerisation temperature of 170xc2x0 C. or less, usually 160xc2x0 C. or less;
It must have a polymerisation time which is as small as possible at the desired polymerisation temperature, for example at most 9 hours at 140xc2x0 C., preferably at most 8 hours. This time is, for example, at most 7 hours at 150xc2x0 C. or at most 6 hours at 160xc2x0 C. The polymerisation time is often at most 6 hours at 150xc2x0 C. or at most 5 hours at 160xc2x0 C.
The requirements mentioned above imply that the formulations used do not contain a polymerisation accelerator.
Water adsorption, which is an important selection criterion within the context of the present invention, is less than 3% at 80xc2x0 C. and usually less than 3% at 100xc2x0 C. This adsorption is preferably less than 2% at these temperatures.
Further, petroleum absorption is generally less than 0.3% at 100xc2x0 C. (API fuel, type II).
The compositions of the invention contain a flow controller. This additive prevents flow of the resin by drainage during hot pressing of several impregnated layers, and also conserves the fibre/matrix volume ratio, which is preferably about 1:1. This ratio is that which produces the best mechanical properties in the composites after polymerisation. This additive can be added using two main methods. The flow controller can be added when mixing the epoxide and the hardener (i.e., before polymerisation). The flow controller is normally selected from the group formed by polyethersulphone type, polyamide type, polyimide type and polyarylsulphone type polymers. The proportion of the flow controller is normally about 1% to 15 % by weight with respect to the final composition weight. These polymers can be mixed using a solvent and, in this case, the epoxide, the hardener and the polymer are in solution on mixing and the solvent is evaporated off after impregnating the walls of the preform. A solvent does not need to be used. In this case, the flow controller is added in two phases:
1) dissolving in the epoxy resin; then
2) adding the amine hardener to this mixture.
Within the context of the present invention, a very reactive hardener can be added to the composition (i.e., a hardener with a reactivity which is higher than the principal hardener and normally very much higher) in small proportions, for example about 1% to 15% by weight, more preferably about 1% to 10% by weight with respect to the total composition weight. In this case, the hardener is added at the last minute, just before impregnation and after adding the flow controller. Thus the cross lining reaction takes place after impregnation and will not affect wetting of the material and will initiate the three-dimensional network with a high dynamic viscosity. The most latent hardener will only react later on heating, for example at 80xc2x0 C. or more, and will terminate cross linking of the resin.
The compositions of the present invention may comprise a proportion of primary aromatic polyamine of about 20 to about 60 parts by weight per 100 parts of epoxy resin, preferably about 25 to about 55 parts per 100 parts of epoxy resin.
With the aim of showing the main advantages brought about by the choice of formulations of the present invention which are described in Examples 2, 3, 4, 5, 7, 8 and 9 below (comprising a flow controller) over formulations which do not contain a flow controller (Examples 1 and 6) and over a prior art formulation (European patent EP-A-0 211 214) comprising 4,4xe2x80x2-diaminodiphenylsulphone (DDS) as a hardener described in comparative Example 10 below, tests were carried out the results of which are shown in Table 2 below. These tests included determining the gel time at three temperatures: 80xc2x0 C., 90xc2x0 C. and 100xc2x0 C. The gel time is the time required at the chosen temperature for a given composition to produce a degree of polymerisation Xg. This degree of polymerisation Xg at the gel point is an important factor as it is linked to a major rheological change due to the irreversible transformation of a viscous liquid to a viscoelastic gel. The gel time is measured using an apparatus sold by PRODEMAT with the trade name TROMBOMAT(copyright) which can determine the gel point and evaluate the reactivity of the hardener from the reaction kinetics.
The dynamic viscosity was measured at 90xc2x0 C. using a PK100(copyright) cone-and-plate viscometer sold by HAAKE.
The glass transition temperature was measured using a KINEMAT(copyright) apparatus sold by PRODEMAT. The rate of temperature increase was 2xc2x0 C. per minute from 20xc2x0 C. to 250xc2x0 C. the glass transition temperature marks the passage from the glassy state to the rubbery state and thus determines the temperature limits of use for the epoxy resins described in Examples 1 to 10. The glass transition temperature measurements were carried out on polymerised samples at 140xc2x0 C. over 8 hours.
Water absorption for epoxy resins manifests itself as a gradual variation in the stiffness of the cross linked network. Fixation of water causes a change in the glass transition temperature and encourages hydrolytic degradation of the epoxy resin and the interfaces between the reinforcing fibres in the walls of the preform. It is thus important that the water absorption of epoxides hardened by aromatic polyamines is as small as possible. Comparative water absorption measurements were carried out on 50xc3x9725xc3x975 millimeter resin samples which had been polymerised for 8 hours at 140xc2x0 C., then impregnated to saturation in distilled water at 100xc2x0 C. Water absorption was measured by the difference in mass at regular intervals until saturation was obtained, i.e., to constant weight, giving the water take-up in percent by weight shown in Table 2 for each composition of Examples 1 to 10.
It is clear that, suprisingly, the compositions of the present invention have a substantially lower water take-up than the water take-up of the reference composition of Example 10 and thus have an undeniable advantage.
The present invention will be better understood, and its advantages will become more clear, from the examples given below.
These tests were carried out using DGEBA epoxy resin manufactured and sold by CIBA under the trade name LY 556(copyright). The principal characteristics of the resin are:
Dynamic viscosity at 25xc2x0 C.: 12 Paxc2x7s;
Epoxide content: 1.15 equivalents per kilogram; and
Density: 1.15 g/cm3.
In order to satisfy the stoichiometry of the reaction, the theoretical quantity of hardener to be introduced into the mixture per 100 grams of epoxide prepolymer had to be calculated. This quantity was termed the xe2x80x9cpwhrxe2x80x9d (parts by weight per hundred grams of resin).
Pwhr=100xc3x97weight equivalent of amine (*)/weight equivalent of epoxy (*)
(*)weight equivalent of reactive hydrogen.
The weight equivalent of epoxy prepolymer was given by the supplier (CIBA): 5.32 equivalent epoxy per kg (i.e., 1000:5.32=187.79 g/mole).
The stoichiometry required the reaction of one molecule of epoxy prepolymer carrying two epoxy groups with two mobile hydrogens of the amine. The primary diamines used in the examples had four mobile hydrogens per molecule. The quantities of amines in pwhr for each amine used are shown in Table 1 below.


Errors in an analog to digital converter that cause generated digital codes to deviate from expected values are corrected. A sample of an analog signal is stored in a storage element. An error signal is then generated, with the error signal representing a deviation of an expected digital code for the strength of a sample of an analog input from a value that would be generated without correction. The error signal is then added to the stored sample. In an embodiment implemented in the context of a SAR ADC, a digital value representing an integral non-linearity error is generated based on a partial digital code (result of a partial conversion of the sample) and an error coefficient. The digital value is converted to analog form by an auxiliary DAC, and added to the stored input sample.

1. Field of the Invention
The present invention relates generally to analog to digital converters (ADC), and more specifically to a technique to correct for errors that cause generated digital codes to deviate from expected values in an ADC.
2. Related Art
Analog to digital converters (ADCs) are used to generate a sequence of digital codes representing the strength of an analog signal at corresponding time instances, and may be implemented according to various techniques such as successive approximation (SAR) ADC, pipelined ADC, etc., as is well known in the relevant arts.
ADCs are generally designed to generate a specific value ("expected value") for a given strength of an analog signal (at the sample time instance). Typically, the ADC is designed to process input signals with a range of strength (often referred as a "dynamic range" of the ADC), and a specific sub-range of strength is associated with each digital code that can be generated by the ADC. The digital code is generally the expected code for the corresponding sub-range of strength.
The digital codes generated by an ADC may deviate from the expected values due to reasons such as non-linearity of various components of an ADC, offset/gain errors, etc., as is well known in the relevant arts. It is generally desirable that the generated digital codes equal the expected values.

Correcting for errors that cause generated digital codes to deviate from expected values in an ADC


A method and system for monitoring the level of flowable material contained in a transportable vessel that utilizes microwave gauging technology. The system includes a microwave lens/seal assembly, a microwave transceiver assembly, a controller/processor assembly and a computer. The lens/seal assembly is permanently secured to the vessel. The microwave transceiver assembly is adapted to be releasably attached to the vessel. The controller/processor assembly and the computer may be located at a loading/unloading facility.

The loading of railway tank cars with liquified gases under pressure, or flowable gases under pressure, or flowable materials for which it is necessary to exclude the escape of vapors, requires that the level of the flowable materials be measured within a sealed tank or vessel. It has been known in the art to utilize various types of mechanical float gauging devices and various types of electrical resistance gauging devices to monitor the level of flowable material being loading into a tank car. These devices generally have components that extend inside the vessel and require contact with the lading.
Microwave technology has been used to continually monitor liquid levels in a stationary vessel. An example of such a device is the CannonBear 1001 Microwave Level Transmitter manufactured by TN Technologies of Round Rock, Tex. This device includes a transceiver unit that is mounted on the top of the vessel and sends a low-level microwave beam toward the surface of liquid in the vessel. Microprocessor-based electronics calculate the time for the reflected signal to return to the transceiver unit to gauge the distance from the transceiver unit to the surface of the liquid in the vessel. The transceiver unit is permanently mounted to the outside of the vessel and a non-conductive and inert process seal or lens separates the transceiver unit from the vessel interior. The transceiver unit is connected to a transmitter electronics which may be remote from the transceiver. Each vessel has a process seal or lens and a transceiver unit permanently mounted thereto.
The advantage of utilizing microwave level transmitter technology to measure the level of flowable materials in a vessel is that no part of the system is in contact with the vessel contents. Also, process material coating, abrasion, temperature change, composition change, density change, and moisture change do not affect the measurement.
There is a need for an improved method and apparatus that utilizes known microwave gauging technology to monitor the level of flowable material contained in a transportable vessel during the loading and unloading thereof at a loading/unloading facility.
As used herein the term "transportable vessel" is intended to include railway tank cars, highway tank trailers, cargo tanks, and the like.

Method and apparatus for monitoring a flowable material in a transportable vessel


In a broadband antenna using a semicircular conductor disc, a semicircular cutout is formed in the semicircular radiator concentrically therewith. Alternatively, a semicircular arcwise radiating conductor with a semicircular cutout defined concentrically therewith is bent into a cylindrical shape to form a radiator.

The present invention relates to an antenna which has a bandwidth as broad as 0.5 to 13 GHz, for instance, but is small in size and, more particularly, relates to an antenna using a semicircular radiator or semicircular, ribbon-shaped radiator.
In R. M. Taylor, "A Broadband Omnidirectional Antenna," IEEE AP-S International Symposium, 1994, p1294, there is disclosed a conventional broadband antenna using semicircular conductor discs as depicted in FIG. 1. This conventional antenna has two elements. One of the elements is composed of two semicircular conductor discs 12.sub.1a and 12.sub.2a, which have a common center line Ox passing through the vertexes of their semicircular arcs and cross at right angles. The other element is also composed of two elements 12.sub.1b and 12.sub.2b, which similarly have a common center line Ox passing through the vertexes of their semicircular arcs and cross at right angles. The two elements are assembled with the vertexes of their circular arcs opposed to each other. A feeding section is provided between the vertexes of the arcs of the two elements; a coaxial cable 31 for feeding is disposed along the center of one of the two elements, with the outer conductor of the cable held in contact with the element.
FIG. 2 illustrates a simplified version of the antenna depicted in FIG. 1, which has semicircular conductor discs 12a and 12b disposed with the vertexes of their semicircular arcs opposed to each other. The feeding section is provided between the vertexes of the two conductor discs 12a and 12b to feed them with the coaxial cable 31 installed in the conductor disc 12b.
FIG. 3 shows the VSWR characteristic of the antenna depicted in FIG. 2. It will be seen from FIG. 3 that the simplified antenna also has a broadband characteristic, which was obtained when the radius r of each of the semicircular conductor discs 12a and 12b was chosen to be 6 cm. The lower limit band with VSWR<2.0 is 600 MHz. Since the wavelength .lambda. of the lower limit frequency in this instance is approximately 50 cm, it is seen that the radius r needs to be about (1/8).lambda.. The radiation characteristic of the antenna shown in FIG. 1 is non-directional in a plane perpendicular to the center line Ox, whereas the radiation characteristic of the antenna of FIG. 2 is non-directional in a frequency region from the lower limit frequency to a frequency substantially twice higher and is highly directive in the same direction as the radiator 12a in the plane perpendicular to the center line Ox.
Thus, the conventional antenna of FIG. 1 comprises upper and lower pairs of antenna elements each formed by two sectorial radiators crossing each other, and hence it occupies much space. Also in the simplified antenna of FIG. 2, the sectorial semicircular radiators are space-consuming. In terms of size, too, the conventional antennas require semicircular conductor discs whose radii are at least around 1/8 of the lowest resonance wavelength; even the simplified antenna requires a 2r by 2r or (1/4).lambda. by (1/4).lambda. antenna area. Accordingly, the conventional antennas have defects that they are bulky and space-consuming and that when the lower limit frequency is lowered, they become bulky in inverse proportion to it.

Broadband antenna using a semicircular radiator


A starting and operating apparatus and method for a sensorless, brushless direct current motor is disclosed. During start-up, the excitation to the motor is turned off while the slope of the differential back electromotive force of the floating phases is sampled. This indicates when the proper rotation and torque of the motor is obtained. After starting the motor, the apparatus samples the slope of the back electromotive force of the floating coils and finds a zero or predetermined slope condition which has been found to be near the optimum switching point for commutation from one phase to the next. A masking circuit is included to prevent an unwanted commutation immediately after commutating to the next phase.

The present invention relates to an apparatus and method for starting and operating a brushless direct current motor, and in particular, starting and operating a brushless direct current motor without the use of add-on sensors. Brushless direct current motors are used in applications such as for disk drives and video cassette recorders and are typically under stringent requirements regarding their performance in these applications. Disk drive manufacturers are concerned with the possibility of having a backward rotation of the motor which may cause warpage of the read-write heads since they are often laying on the disk when it rests. This invention is directed to starting such a motor. Another requirement of users of these motors is that the torque of the motor is optimized once the correct direction of rotation during start-up is achieved. Failure to maximize the torque may cause losing control of the motor, ripple on the speed or loss of efficiency, which is not acceptable for applications, such as, portable, battery-operated systems.
The use of sensors such as Hall-sensors to detect the rotation of the motor, for example, as known in the art, often results in diminished performance of the motor with the offset of the Hall-sensor and errors due to the positioning of the Hall-sensor inside the motor.
Motor driving circuits utilizing the back-electromotive force sensing principle give an alternative to the use of sensors for motor driving circuits.
One such motor driving circuit based on the back-electromotive force sensing principle is disclosed in an article entitled "A Full-Wave Motor Drive IC Based on the Back-EMF Sensing Principle", by J. P. M. Bahlmann, IEEE Transactions on Consumer Electronics, Vol. 35, No. 3,Aug. 1989, pp. 415-420. The Bahlmann full-wave motor drive utilizes a bipolar integrated circuit which has been designed to allow full-wave driving of brushless three-phase DC motors. Three push-pull power stages are operated in a switching mode. The commutation moments are derived from the zero-crossings of the sensed back-electromotive force in the floating motor windings. A start-up system is also disclosed which generates commutations when no zero-crossing can be detected. Problems may occur, though in utilizing zero-crossing of the floating phase due to common mode signals especially during starting of the motor.

Brushless direct current motor starting and operating apparatus and method


A signal processing method is disclosed. The method includes identifying a preferred loss profile for a plurality of signal transmission channels and generating a filter transfer function corresponding to each of the plurality of signal transmission channels, where each filter transfer function is configured to produce a filtered signal with a loss profile approximately equal to the preferred loss profile. The method further includes generating a plurality of filtered signals by filtering a plurality of signals using the filter transfer function corresponding to each of the plurality of signal transmission channels. and transmitting the plurality of filtered signals to a plurality of receivers via the plurality of signal transmission channels.

As the value and use of information continues to increase, individuals and businesses seek additional ways to process and store information. One option available to users is information handling systems. An information handling system generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes thereby allowing users to take advantage of the value of the information. Because technology and information handling needs and requirements vary between different users or applications, information handling systems may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in information handling systems allow for information handling systems to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. For example, an information handling system may be a tablet computer or mobile device (e.g., personal digital assistant (PDA) or smart phone) configured to transmit data on a wireless communications network. Information handling systems may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
Many different types of channels and signal transmission methods may be used to transmit data between components of an information handling system. The channels over which the signals are transmitted may negatively affect signal integrity. For example, certain channels may be prone to frequency loss and/or high reflectivity, both of which may degrade and/or attenuate the data signal.

System and method of enhancing signal integrity


An energy storage mechanism for folding seats for vehicles and the like includes an energy-storing component such as a spring that assists in moving the seat or other component. The mechanism provides for relatively small user input forces and distances, yet provides a relatively large force acting over a relatively large distance as an output of the mechanism. The mechanism may be configured to provide for a single user input/release, without requiring powered actuators or the like.

Various mechanisms for moving and/or folding seats for motor vehicles have been developed. One type of seat that may be used in Sport Utility Vehicles ("SUVs"), vans or the like includes one or more mechanisms that enable the seat back to be folded down, followed by upward and forward rotation of the seat back and base. Such seats provide for increased space for transporting large objects or the like when the rear seats of the vehicle are not needed.
Although such seats have been widely used due to the need for increased space, known mechanisms may not fully assist the user in folding the seat. Thus, known folding seat arrangements may require substantial input of force by a user to fold and/or unfold the seat.
Electrically-powered folding seats have also been developed, but the electrical actuators and related electrical components tend to be more costly than known mechanical mechanisms. Due to the added complexity, weight, and extra expense, powered folding seats have had somewhat limited acceptance in the marketplace.


A method performed by a User Equipment (UE) is performed. The UE obtains (202) a beam reporting configuration. The beam reporting configuration defines a beam reporting procedure for determining an optimal beam for each of different sub-bands of a system bandwidth. The UE measures (204) different reference signals transmitted by the network node. The measured different reference signals correspond to each of the different sub-bands according to the beam reporting configuration. The UE then determines (206) a preferred beam for each of the different sub-bands based on the corresponding received reference signals.

In a typical wireless communication network, User Equipments (UE), also known as wireless communication devices, mobile stations, stations (STA) and/or wireless devices, communicate via a Radio Access Network (RAN) and/or a Local Area Network such as a WiFi network or to one or more core networks (CN). The RAN covers a geographical area which is divided into service areas or cell areas, which may also be referred to as a beam or a beam group, with each service area or cell area being served by a radio network node such as a radio access node e.g., a Wi-Fi access point or a radio base station (RBS), which in some networks may also be denoted, for example, a NodeB, eNodeB (eNB), or gNB as denoted in 5th Generation (5G). A service area or cell area is a geographical area where radio coverage is provided by the radio network node. The radio network node communicates over an air interface operating on radio frequencies with the wireless device within range of the radio network node. The radio network node communicates to the wireless device in DownLink (DL) and from the wireless device in UpLink (UL).
Specifications for the Evolved Packet System (EPS), also called a Fourth Generation (4G) network, have been completed within the 3rd Generation Partnership Project (3GPP) and this work continues in the coming 3GPP releases, for example to specify a Fifth Generation (5G) network also referred to as 5G New Radio (NR). The EPS comprises the Evolved Universal Terrestrial Radio Access Network (E-UTRAN), also known as the Long Term Evolution (LTE) radio access network, and the Evolved Packet Core (EPC), also known as System Architecture Evolution (SAE) core network. E-UTRAN/LTE is a variant of a 3GPP radio access network wherein the radio network nodes are directly connected to the EPC core network rather than to RNCs used in 3rd Generation (3G) networks. In general, in E-UTRAN/LTE the functions of a 3G RNC are distributed between the radio network nodes, e.g. eNodeBs in LTE, and the core network. As such, the RAN of an EPS has an essentially "flat" architecture comprising radio network nodes connected directly to one or more core networks, i.e. they are not connected to RNCs. To compensate for that, the E-UTRAN specification defines a direct interface between the radio network nodes, this interface being denoted the X2 interface.
Multi-antenna techniques may significantly increase the data rates and reliability of a wireless communication system. The performance is in particular improved if both the transmitter and the receiver are equipped with multiple antennas, which results in a Multiple-Input Multiple-Output (MIMO) communication channel. Such systems and/or related techniques are commonly referred to as MIMO.
In addition to faster peak Internet connection speeds, 5G planning aims at higher capacity than current 4G, allowing higher number of mobile broadband users per area unit, and allowing consumption of higher or unlimited data quantities in gigabyte per month and user. This would make it feasible for a large portion of the population to stream high-definition media many hours per day with their mobile devices, when out of reach of Wi-Fi hotspots. 5G research and development also aims at improved support of machine to machine communication, also known as the Internet of things, aiming at lower cost, lower battery consumption and lower latency than 4G equipment.
In addition to faster peak Internet connection speeds, 5G planning aims at higher capacity than current 4G, allowing higher number of mobile broadband users per area unit, and allowing consumption of higher or unlimited data quantities in gigabyte per month and user. This would make it feasible for a large portion of the population to stream high-definition media many hours per day with their UEs, when out of reach of Wi-Fi hotspots. 5G research and development also aims at improved support of machine to machine communication, also known as the Internet of things, aiming at lower cost, lower battery consumption and lower latency than 4G equipment.
For a given communication link, a beam may be applied at both a Transmit Receive Point (TRP) and a UE. This TRP-UE may be referred to as a Beam Pair Link (BPL). Due to frequency selectivity in a channel, the optimal TRP Transmit (TX) beam may be different for different parts of the system frequency band. Hence, depending on in which frequency sub-band the UE is scheduled in, different TRP TX beams may be optimal relative to others.
In current beam management techniques, a UE transmits only one Channel State Information Reference Signal (CSI-RS) Resource Indicator (CRI) report to the TRP, e.g. network node, for the entire bandwidth. Hence, the TRP is unable to determine which TRP TX beam is optimal for a particular sub-band of the greater system bandwidth.

UE, network node and methods therein for beam reporting in a wireless communication system


A system and method for analyte measurement is provided. The system includes: a transimpedance amplifier including: at least one operational amplifier including a first input coupling to a reference voltage, a second input coupling to a sensor for sensing the analyte, and an output; and at least one passive circuit element having a first terminal and a second terminal, the first terminal of the at least one passive circuit element coupling to the second input of the at least one operational amplifier, and a circuit for adjusting a gain of the transimpedance amplifier for the measurement of the analyte. The method includes: monitoring a level of the output of the at least one operational amplifier for the measurement of the analyte; and adjusting a gain of the transimpedance amplifier during the measurement of the analyte.

A blood glucose meter is used by individuals to measure the concentration of glucose in their blood. People with diabetes have a special interest in measuring the concentration of glucose as the level of glucose can be an indication of whether treatment of their diabetes is required or not.
Handheld, commercially available blood glucose meters are typically used for this purpose. Such commercially available meters work by having the patient place a small blood drop on a test strip (a "sensor"). Then the test strip is inserted in a glucose meter followed by processing of the test strip in the glucose meter to determine the concentration of the glucose.
In typical operation, the sensor will produce a small current (known as "work current") when biased with a voltage. The current will vary as function of the chemical reaction happening in the test strip. This variation can have a very large dynamic range, leading to a possible saturation on the output of the sensor interface. Therefore there is a need to adjust the operation of the electro-chemical sensor interface to accommodate such large variations in work currents without the sensor interface saturating.

System and method for gain adjustment in transimpedance amplifier configurations for analyte measurement

Semiconductor Components Industries, LLC


In one aspect, the present invention provides a process for producing a sodium salt of an immunosupressant of Formula I

Mycophenolic acid is an immunosuppressive agent that inhibits de novo purine nucleotide synthesis via inhibition of IMP dehydrogenase and prevents the formation of XMP and GMP.
Mycophenolic acid sodium salt or ERL 080 has been widely discussed in available patent and non-patent literature, for its use in treatment of diseases and transplantation.
The use of Mycophenolalic acid sodium salt in the treatment of hyperuricaemia has been reported in U.S. Pat. No. 3,705,946. U.S. Pat. No. 6,025,391 describes an enteric coating composition, containing HPMC phthalate and triacetin prepared for capsules containing monosodium mycophenolate, and adapted to release mycophenolate in the upper part of the intestinal tract.
The tolerability profile of sodium mycophenolate and mycophenolate mofetil with and without cyclosporin has been discussed in Toxicology 157(2001) 207–215.
The Journal Acta Crystallographica, Section C: Crystal Structure Communications (2000), C56(4), 432–433, discusses a crystal stucture of sodium mycophenolate.

Process for the production of an immunosuppressant


Barrier structure placeable as a projectile-disabling, anti-liquid-leakage protective shield for the outside surface of a container designed to hold liquid of a certain nature including (a) a first-type (innermost) layer formed as an expanse of high-elastomeric material which is substantially fully self-healing via elastomeric behavior with regard to a piercing projectile wound, (b) a second-type (intermediate) layer disposed adjacent one side of the first-type layer as an expanse including a body of substantially the same high-elastomeric material in which there is contained a distribution of liquid-imbiber beads which react, and expand three-dimensionally in relation, to contact with liquid of the mentioned certain nature, and (c) a third-type (outermost) layer disposed adjacent the second-type layer, and formed as an expanse of substantially the same high-elastomeric material employed in the first- and second-type layers. In one embodiment of the invention, these layers are dimensioned whereby the first- and third-type layers each possesses a thickness substantially twice that of the second-type layer, and in a second invention embodiment, no matter the thickness of the innermost layer, that of the outermost layer is substantially twice that of the intermediate layer.

This invention pertains to a special, self-healing, anti-liquid-leakage projectile barrier structure, and to a related methodology. In particular, it pertains to specific, improved and now recognized forms of the layered barrier structure described in the '723 patent application.
While there are many applications and situations wherein the present invention offers important utility, a preferred and best mode embodiment of, and manner of practicing, the invention are described herein in the setting of an intended disabling projectile attack, such as a sniper bullet attack, on the otherwise exposed fuel tanks in certain types of military vehicles. Although this military environment provides an excellent vehicle for describing the present invention, those skilled in the art will quickly understand from the disclosure herein how the structure and methodology of the invention may be employed with respect to other types of liquid-containing structures (i.e., ground storage tanks, pipelines, etc.).
With respect to this illustrative military use of the present invention, a tactic employed in combat involves directing sniper fire at a vehicle's exposed fuel tank or container. Bullet penetration of such a fuel tank initiates fuel leakage when a puncture occurs, and successful sniper fire which has achieved a puncture in such a tank may then be followed by the firing of incendiary rounds which ignite a catastrophic and life-threatening fire.
According to the present invention, a selected exposed surface of such a tank, or container, is appropriately coated with a multi-layer (and as proposed by the present invention, preferably three-layer), self-healing/self-sealing barrier structure which lies at the heart of the present invention. This layer structure is "sandwich-like" in form. It includes two, outer bracketing layers formed of a high-elastomeric material, with a third, intermediate layer formed as a composite-material layer having a body made of the same high-elastomeric material used in the outer layers, and imbedded within this body, a distribution of bead-like elements (called beads herein) which respond to contact with the usual hydrocarbon fuel to undergo rapid absorption of any leaking fuel, accompanied by rapid, three-dimensional physical enlargement as a consequence of such liquid absorption.
Preferably, the elastomeric material just mentioned is capable, within its range of elasticity, of easily undergoing about a 400-percent stretch. A very suitable material for this purpose is a two-part, bendable product sold under the trademark TUFF STUFF®, and made by Rhino Linings USA, Inc. in San Diego, Calif. Specific product designations for such a two-part Rhino-Linings product are 60012 and 60058.
With respect to the mentioned distribution of bead-like elements, a very suitable material takes the form of what are referred to as liquid-imbiber beads which react to hydrocarbon fuel in the manner mentioned above, and which are made by a company known as Imbibitive Technologies America, Inc. in Midland, Mich. A particular liquid-imbiber-bead product made by this company, and very suitable for use, is a product which is sold under that company's product identification IMB230300.
Those skilled in the art will certainly recognize from the description given below how different, specific elastomeric materials and imbiber, bead-like elements may be selected and used for different kinds of potential liquid leakage.
The present invention specifically focuses upon improved layer-thickness configurations for the basic barrier structure innovation described in certain ones of the above-cross-referenced, prior patent applications. Very specifically, and referring to one preferred form, or embodiment, of the present invention, we have discovered that, within certain ranges of composite-layer thicknesses, a very successfully performing multi-layer (i.e., composite-layer) arrangement includes two outer (innermost and outermost bracketing layers) high-elastomeric layers which possess a common thickness which is substantially twice that of the intermediate composite layer. We have found that a very appropriate range of thicknesses useable for the two outer elastomeric layers is about ¼-inches to about ¾-inches, and that an appropriate related range of layer thicknesses for the intermediate composite layer is about ⅛-inches to about ⅜-inches. With respect to the military-situation conditions described above herein, we have further found that a preferred layer organization is one wherein there is a common layer thickness for each of the two outer layers in the composite, plural-layer structure of the proposed barrier structure, which common thickness is about ¼-inches, with the intermediate composite layer having a thickness of about ⅛-inches.
Another discovery about an improved form of layer arrangement involves a plural-layer composite structure wherein, regardless of innermost layer thickness, so long as that thickness is about ⅛-inches, the outermost layer thickness is about twice that of the intermediate layer thickness. For example, we have found that, for certain applications, this other, preferred, composite layer arrangement can be realized with an innermost layer thickness of about ⅛-inches, an intermediate layer thickness in the range of about ⅛-inches to about 3/16-inches, and an outermost layer thickness (preferably in a 2:1 ratio with the thickness of the intermediate layer) in the range of about ¼-inches to about ⅜-inches, and with an overall composite layer thickness preferably being no less than approximately ⅝-inches.
The various features, advantages, and operating mechanisms which characterize the present invention will now become more fully apparent as the description which follows below is read in conjunction with the single accompanying drawing FIGURE.


Methods and systems are provided for reducing exhaust temperatures during high engine load conditions in engine systems configured to operate with multiple fuels. Stoichiometric cylinder operation is provided via injection of a gaseous fuel such as CNG. In response to elevated exhaust temperatures, the cylinder is enriched by injecting a liquid fuel, such as gasoline, while maintaining the injection of CNG and while maintaining spark timing at MBT.

Alternate fuels have been developed to mitigate the rising prices of conventional fuels and for reducing exhaust emissions. For example, natural gas has been recognized as an attractive alternative fuel. For automotive applications, natural gas may be compressed and stored as a gas in cylinders at high pressure. Various engine systems may be used with CNG fuels, utilizing various engine technologies and injection technologies that are adapted to the specific physical and chemical properties of CNG fuels. For example, mono-fuel engine systems may be configured to operate only with CNG while multi-fuel systems may be configured to operate with CNG and one or more other fuels, such as gasoline or gasoline blend liquid fuels. Engine control systems may operate such multi-fuels systems in various operating modes based on engine operating conditions.
One example multi-fuel system is described by Surnilla et al. in U.S. Pat. No. 7,703,435. Therein, an engine is configured to operate on CNG, gasoline, or a mixture of both. Fuel is selected for operating the engine during particular operating conditions based on the amount of fuel available in each fuel storage tank as well as based on the type and attributes of the available fuel. For example, vehicle mileage can be extended by selecting a particular fuel during high driver demand. As another example, engine emissions can be improved by reserving a particular fuel for engine starting conditions.
However the inventors herein have recognized that the approach of '435 may not leverage all the attributes of the available fuels. For example, the approach does not take into consideration the flammability limits of the available fuels. Since the flammability limits of each fuel have an effect on the fuel's octane, torque output, and knock addressing ability, the fuel injection profiles selected may have torque loss issues, knock resistance issues, and/or may require the use of substantial spark retard. As such, any of these may result in reduced fuel economy.
In one example, some of the above issues may be addressed by an engine method that leverages all the attributes of the available fuels, including the flammability limits. The method comprises, during high load conditions, when operating with a first gaseous fuel, in response to an elevated exhaust temperature, enriching the engine via injection of a second, liquid fuel while maintaining spark timing.
As an example, an engine may be configured to operate on a first, gaseous fuel, such as CNG, and a second, liquid fuel, such as gasoline. During high load conditions, the engine may be operating on at least some CNG to provide benefits that minimize the consumption of liquid fuel while meeting the torque demand. In other words, the system may be configured to preferentially use the low cost, high octane gaseous fuel. For example, CNG may be port injected into an engine cylinder, the port injection based on the intake air received in the cylinder so as to operate the cylinder with a combustion air-fuel ratio that is substantially at or around stoichiometry. In response to elevated exhaust temperatures experienced while operating at high engine loads, exhaust cooling may be achieved by enriching the engine cylinder via increased injection of the liquid fuel. For example, as the exhaust temperature increases above a threshold temperature, gasoline may be direct injected into the cylinder to provide a combustion air-fuel ratio that is richer than stoichiometry. At the same time, injection of CNG may be maintained while also maintaining spark timing at MBT. For example, while operating the cylinder with 100% CNG (that is, fueling with CNG corresponding to 100% of the intake air amount) to meet the torque demand, the cylinder may be enriched using up to 15% gasoline (that is, fueling with additional gasoline corresponding to 15% of the intake air amount). While the example is referenced as 100% CNG and 15% gasoline, the same may also be alternatively represented as a fuel split of 87% CNG and 13% gasoline at 15% overall richness.
This approach provides various benefits. First, the octane of CNG can be used to meet the torque demand without need for spark retard while the wider flammability limit of gasoline (e.g., in the range of 0.6 to 1.5 lambda) is advantageously used to cool the exhaust. By using CNG to power the engine and gasoline to cool the engine, a smaller degree of enrichment is needed to cool the engine than would have otherwise been required if the engine were operating with only gasoline. As such, this improves fuel economy. By reducing the need for spark retard (which would have otherwise been required if the engine were operating with only gasoline), torque losses and power losses are reduced. By also reducing the need for throttle adjustments (which would have otherwise been required to reduce the exhaust temperature), torque losses due to lower intake air charge are also reduced. Overall, exhaust cooling is achieved without suffering power losses and without degrading fuel economy.
It should be understood that the summary above is provided to introduce in simplified form a selection of concepts that are further described in the detailed description. It is not meant to identify key or essential features of the claimed subject matter, the scope of which is defined uniquely by the claims that follow the detailed description. Furthermore, the claimed subject matter is not limited to implementations that solve any disadvantages noted above or in any part of this disclosure.


A GaP red light emitting diode (LED) which is free from a problem of luminance reduction comprises an n-type GaP epitaxial layer grown on an n-type GaP substrate, and a p-type GaP epitaxial layer grown on the n-type Gap epitaxial layer, wherein the n-type epitaxial layer has an Si concentration of not more than 5.times.10.sup.17 atoms/cc and an S concentration of not more than 1.times.10.sup.18 atoms/cc.

1. Field of the Invention
The present invention relates to a GaP red light emitting diode (LED) having a high luminance level.
2. Description of the Prior Art
Heretofore, GaP red LEDs have generally been fabricated by the liquid-phase epitaxial growth method. In this epitaxial growth method, an n-type GaP epitaxial layer doped with Te is grown on an n-type GaP substrate. Subsequently, from a Ga melt added with Zn and Ga.sub.2 O.sub.3, a p-type GaP epitaxial layer is grown and deposited on the n-type GaP epitaxial layer, thus making a p-n junction. The resulting crystal is annealed at about 500.degree. C. with the result that Zn-O pairs are created. The Zn-O pairs form an emission center from which red light is emitted.
The GaP LEDs of the type described often cause a problem of luminance reduction or drop and, hence, a satisfactory solution of this problem has been desired. However, there have been considerable difficulties in clearing up factors having direct connection with the luminance reduction.
Through a lengthy and careful investigation on the cause of the luminance reduction of the GaP red LEDs, the present inventors uncovered the fact that the luminance reduction is closely related to the impurity concentration of the n-type epitaxial layer, more particularly to the Si concentration and S concentration. Based on this finding, the present invention was made.