Disclosed are implants, stents, catheters, methods and kits for the local delivery of therapeutic agents that are preferentially cytotoxic or cytostatic with regards to proliferating cells to sites where proliferative cells are present.

1. Field of the Invention
The present invention relates to the local delivery of therapeutic agents that are preferentially cytotoxic or cytostatic with regards to proliferating cells.
2. Description of Related Art
Uncontrolled cell proliferation can be a serious problem. For example, one form of uncontrolled cell proliferation is cancer, which is second only to cardiac disease as a cause of death in the United States. Another form of uncontrolled cell proliferation is restenosis, which can be life threatening if not treated.
Researchers have developed a series of therapeutic agents for systemic treatment of cancer. Two therapeutic agents of interest are camptothecin and taxol.
20(S)-camptothecin (CPT), a plant alkaloid, was found to have anticancer activity in 1966 (Wall, M., Wani, M. C., Cooke, C. E., Palmer, K. H., McPhail, A. T. and Slim, G. A. xe2x80x9cPlant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminataxe2x80x9d, J. Am. Chem. Soc. 88: 3888-3890, 1966).
During the sixties and seventies the sodium salt of CPT was derived from CPT, and clinical trials of this chemically altered CPT were carried out and then abandoned because of the high toxicity and low potency of this compound (Gottlieb, J. A., Guarino, A. M., Call, J. B., Oliverio, V. T. and Block, J. B. xe2x80x9cPreliminary pharmacological and clinical evaluation of camptothecin sodium salt (NSC 100880)xe2x80x9d, Cancer Chemother. Rep. 54: 461-470; 1979; Muggia, F. M., Creaven, P. J., Hansen, H. H., Cohen, M. N. and Selawry, D. S. xe2x80x9cPhase I clinical trials of weekly and daily treatment with camptothecin (NSC 100880). Correlation with clinical studies.xe2x80x9d Cancer Chemother. Rep. 56: 515-521; 1972; Gottlieb, J. A. and Luce, J. K. xe2x80x9cTreatment of malignant melanoma with camptothecin (NSC 100880).xe2x80x9d Cancer Chemother. Rep. 56: 103-105; 1972; and Moertel, C. G., Schutt, A. J., Reitemeier, R. J. and Hahn, R. G. xe2x80x9cPhase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinal cancer.xe2x80x9d Cancer Chemother Rep. 56: 95-101; 1972.
All these trials were conducted using the hydrosoluble, sodium salt derivative of CPT (CPT Na+), which was administered intravenously. The net result of this research established the ineffectiveness and the toxicity of CPT Na+.
Drug therapies have been evaluated with respect to treating human cancer, e.g., human cancer xenograft lines. Human tumors are serially heterotransplanted into immunodeficient, so-called xe2x80x9cnudexe2x80x9d mice, and the mice then tested for their responsiveness to a specific drug. (Giovanella, B. C., et al., Cancer 52(7): 1146(1983)). The data obtained in these studies strongly support the validity of heterotransplanted human tumors into immunodeficient mammals, such as nude mice, as a predictive model for testing the effectiveness of anticancer agents.
It was determined that 9-Amino-20(S)-Camptothecin (9AC) and 10,11-Methylendioxy-20(S)-Camptothecin (10,11 MD) are capable of having high anticancer activity against human colon cancer xenografts (Giovanella, B. C., Wall, M. E., Wani, M. C. Nicholas, A. W., Liu, L. F., Silber, R. and Potmesil, M. xe2x80x9cHighly effective topoisomerase-I targeted chemotherapy of human colon cancer in xenografts.xe2x80x9d Science 246: 1046-1048; 1989).
U.S. Pat. No. 5,552,154 to Giovanella et al. disclosed methods of treating specific forms of cancer with water-insoluble 20(S)-camptothecin and derivatives thereof, having the closed-lactone ring intact. In particular, transdermal, oral and intramuscular methods of administration using solutions of water-insoluble 20(S)-camptothecin were disclosed.
However, these methods of administration are all systemic, and therefore can create undesirable systemic side-effects.
Taxol is a naturally occurring compound which has shown promise as an anti-cancer drug. For example, taxol has been found to be an active agent against drug-refractory ovarian cancer by McGuire et al. See xe2x80x9cTaxol: A Unique Anti-Neoplastic Agent With Significant Activity Against Advanced Ovarian Epithelial Neoplasms.xe2x80x9d Ann. Int. Med., 111. 273-279 (1989).
Unfortunately, taxol has extremely low solubility in water, which makes it difficult to provide a suitable dosage form. In fact, in Phase I clinical trials, severe allergic reactions were caused by the emulsifiers administered in conjunction with taxol to compensate for taxol""s low water solubility; at least one patient""s death was caused by an allergic reaction induced by the emulsifiers. Dose limiting toxicities include neutropenia, peripheral neuropathy, and hypersensitivity reactions.
These investigations showed that systemic administration of taxol can result in severe systemic side-effects, which limits the usefulness of taxol in a clinical setting.
Furthermore, the investigations into CPT and taxol, as discussed above, focused primarily on the use of these materials as anti-cancer agents. By way of comparison, fairly little work has been done with these materials in the area of restenotic lesions.
Restenosis may be defined as the reclosure of a previously stenosed and subsequently dilated peripheral or coronary vessel. It may occur at a rate of 20-50% for these procedures and is dependent on a number of clinical and morphological variables. Restenosis may begin shortly after a stenosing procedure, and tends to cease after about 4-12 months thereafter. Several hypotheses exist on why and how restenosis occurs. Some researchers believe that restenosis is a natural healing process in response to the injury that occurs during a stenosing procedure. The problem associated with this healing process is that, in some instances, it does not shut off. the artery continues to xe2x80x9chealxe2x80x9d until it becomes occluded by proliferating cells.
Unfortunately, there has been only marginal success in the treatment of restenosis, particularly in the area of restenosis of coronary arteries.
There is therefore a need for apparatus, methods and kits for the treatment of proliferating cells, such as cancerous or restenotic cells, to resolve the aforementioned problems.
This invention relates to implants for administering at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells comprising an implant structure and at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells.
In another aspect, this invention relates to stents comprising at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells. Additionally, this invention relates to a method of treatment comprising inserting a stent into a lumen of a body, wherein the stent comprises at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells.
In still another aspect, the invention relates to an apparatus comprising an intraluminal catheter and a supply of at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells. Additionally, the invention relates to an apparatus comprising a container adaptable for connection to an intraluminal catheter, wherein the container contains at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells.
Furthermore, the invention relates to a method of treatment comprising administering at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells through an intraluminal catheter. In addition, the invention relates to a kit comprising a container adaptable for connection to an intraluminal catheter, wherein the container contains at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells.
In one aspect, the invention relates to an implant for administering at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells comprising an implant structure and at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells. Additionally, the invention relates to implants where the implant is a time-release implant, or is a gel or polymer implant.
In yet another aspect, the invention concerns implants where the therapeutic agents comprise agents that interrupt cell replication and those that prevent or limit chemotaxis. In a further aspect, the invention concerns implants where the therapeutic agent comprises at least one of camptothecin, taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention additionally relates to implants where the therapeutic agent comprises methotrexate, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. Further, the invention relates to implants where the therapeutic agent comprises mitoxantrone, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. Additionally, the invention concerns implants wherein the at least one therapeutic agent is camptothecin, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof.
In still another aspect, the invention relates to implants wherein the therapeutic agent is camptothecin. In addition, the invention concerns implants wherein the therapeutic agent is 9-nitro-20(S) camptothecin. In yet another aspect, the invention concerns implants wherein the therapeutic agent is 9-amino-20(S) camptothecin.
The invention also concerns implants wherein the at least one therapeutic agent is taxol, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. Further, the invention concerns implants where the implant is coated and the therapeutic agent is contained in the coating. In addition, the invention concerns implants where the therapeutic agent is contained within the implant structure.
In another aspect, the invention relates to implants wherein the therapeutic agent is present in an amount effective to reduce cell proliferation once the implant is deployed. Furthermore, the invention relates to implants where the cell proliferation that is reduced is restenotic or cancerous. In other aspects, the invention is relates to implants where the implant is biodegradable or is formed in situ.
Additionally, the invention concerns methods of treatment comprising inserting an implant into a lumen in a body wherein the implant is the implant disclosed above. Furthermore, the invention concerns these methods where the therapeutic agent comprises at least one of camptothecin, taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
In an aspect, the invention relates to these methods where the therapeutic agent comprises methotrexate, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. In another aspect, the invention relates to these methods where the therapeutic agent comprises mitoxantrone, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
Furthermore, the invention concerns these methods wherein the at least one therapeutic agent is camptothecin, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. In still another aspect, the invention concerns these methods wherein the therapeutic agent is camptothecin. Additionally, the invention relates to these methods wherein the therapeutic agent is 9-nitro-20(S) camptothecin. Further, the invention concerns these methods wherein the therapeutic agent is 9-amino-20(S) camptothecin. In still another aspect, the invention concerns these methods wherein the at least one therapeutic agent is taxol, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof.
Additionally, the invention concerns these methods where the therapeutic agent is contained within the stent structure. In another aspect, the invention relates to these methods wherein the therapeutic agent is present in an amount effective to reduce cell proliferation once the stent is deployed. In still another aspect, the invention relates to these methods where the cell proliferation that is reduced is restenotic or cancerous.
Further, the invention concerns these methods where the methods are used to treat restenosis, various types of cancers, insults to body tissue due to surgery, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.
Additionally, the invention concerns these methods where the methods are used to treat coronary, carotid, and cerebral restenotic lesions. In still another aspect, the invention relates to these methods where the methods are used to treat gliomas, other central nervous system tumors, tumors at localized sites including inoperable tumors, tumors where localized treatment of tumors would be beneficial, and solid tumors. In an aspect of the invention, these methods are disclosed as useful to treat cell proliferation associated with joint surgery, bowel surgery, and cheloid scarring. In another aspect of the invention, these methods are disclosed as useful to treat emphysema. In still another aspect, the invention relates to these methods where the methods are used to treat carpal tunnel syndrome. Further, the invention is concerned with these methods where the methods are used to treat disorders of tissues that are not highly vascularized. Additionally, the invention relates to these methods where the methods are used to treat proliferative responses contributing to potential organ rejections or associated complications. Further, the invention concerns the methods where the method is used to treat proliferative responses occurring as a result of transplantation of the heart, lung, liver, kidney, and other body organs or organ systems.
In addition, the invention concerns a kit comprising an implant and a mechanism capable of inserting the implant into a lumen of a body, wherein the implant is the implant as disclosed above. In an aspect, the invention relates to these kits wherein the mechanism is an intraluminal catheter. In another aspect, the invention concerns these kits where the therapeutic agents comprise agents that interrupt cell replication and those that prevent or limit chemotaxis. In still another aspect, the invention relates to these kits where the therapeutic agent comprises at least one of camptothecin, taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to these kits where the therapeutic agent comprises methotrexate, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention further relates to these kits where the therapeutic agent comprises mitoxantrone, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention also relates to these kits wherein the at least one therapeutic agent is camptothecin, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. The invention additionally relates to these kits wherein the therapeutic agent is camptothecin. The invention also relates to these kits wherein the therapeutic agent is 9-nitro-20(S) camptothecin. The invention also relates to these kits wherein the therapeutic agent is 9-amino-20(S) camptothecin.
The invention additionally relates to these kits wherein the at least one therapeutic agent is taxol, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. The invention also relates to these kits where the implant is coated and the therapeutic agent is contained in the coating.
The invention also relates to these kits where the therapeutic agent is contained within the implant structure. The invention also relates to these kits wherein the therapeutic agent is present in an amount effective to reduce cell proliferation once the implant is deployed. The invention also relates to these kits where the cell proliferation that is reduced is restenotic or cancerous. The invention also relates to these kits where the stent is biodegradable or is formed in situ.
In another aspect, the invention relates to a stent comprising at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells. The invention also relates to these stents where the therapeutic agents comprise agents that interrupt cell replication and those that prevent or limit chemotaxis. The invention also relates to these stents where the therapeutic agent comprises at least one of camptothecin, taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to these stents where the therapeutic agent comprises methotrexate, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention also relates to these stents where the therapeutic agent comprises mitoxantrone, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to these stents wherein the at least one therapeutic agent is camptothecin, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. The invention further relates to these stents wherein the therapeutic agent is camptothecin. The invention also relates to these stents wherein the therapeutic agent is 9-nitro-20(S) camptothecin. The invention also relates to these stents wherein the therapeutic agent is 9-amino-20(S) camptothecin.
In another aspect, the invention concerns these stents wherein the at least one therapeutic agent is taxol, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. Further, the invention relates to these stents where the stent is coated and the therapeutic agent is contained in the coating. The invention also relates to these stents where the therapeutic agent is contained within the stent structure. The invention also relates to these stents wherein the therapeutic agent is present in an amount effective to reduce cell proliferation once the stent is deployed. The invention also relates to these stents where the cell proliferation that is reduced is restenotic or cancerous. The invention also relates to these stents where the stent is biodegradable or is formed in situ.
In another aspect, the invention relates to methods of treatment comprising inserting a stent into a lumen of a body, wherein the stent comprises at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells. The invention also relates to these methods where the therapeutic agent comprises at least one of camptothecin, taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to these methods where the therapeutic agent comprises methotrexate, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention also relates to these methods where the therapeutic agent comprises mitoxantrone, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention also relates to these methods wherein the at least one therapeutic agent is camptothecin, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. The invention also relates to these methods wherein the therapeutic agent is camptothecin. The invention also relates to these methods wherein the therapeutic agent is 9-nitro-20(S) camptothecin. The invention also relates to these methods wherein the therapeutic agent is 9-amino-20(S) camptothecin.
The invention also relates to these methods wherein the at least one therapeutic agent is taxol, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. The invention-also relates to these methods where the therapeutic agent is contained within the stent structure. The invention also relates to these methods wherein the therapeutic agent is present in an amount effective to reduce cell proliferation once the stent is deployed. The invention also relates to these methods where the cell proliferation that is reduced is restenotic or cancerous.
The invention also relates to these methods where the method is used to treat restenosis, various types of cancers, insults to body tissue due to surgery, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants. The invention also relates to these methods where the method is used to treat coronary, carotid, and cerebral restenotic lesions. The invention also relates to these methods where the method is used to treat gliomas, other central nervous system tumors, tumors at localized sites including inoperable tumors, tumors where localized treatment of tumors would be beneficial, and solid tumors.
The invention also relates to these methods where the method is used to treat cell proliferation associated with joint surgery, bowel surgery, and cheloid scarring. The invention also relates to these methods where the method is used to treat emphysema. The invention also relates to these methods where the method is used to treat carpal tunnel syndrome. The invention also relates to these methods where the method is used to treat disorders of tissues that are not highly vascularized. The invention also relates to these methods where the method is used to treat proliferative responses contributing to potential organ rejections or associated complications.
The invention also relates to these methods where the method is used to treat proliferative responses occurring as a result of transplantation of the heart, lung, liver, kidney, and other body organs or organ systems. The invention also relates to these methods where the stent is biodegradable or is formed in situ.
The invention also relates to kits comprising a stent and a mechanism capable of introducing the stent into a lumen of a body, wherein the stent is the stent disclosed above. In another aspect, the invention relates to these kits wherein the mechanism is an intraluminal catheter. The invention also relates to these kits where the therapeutic agents comprise agents that interrupt cell replication and those that prevent or limit chemotaxis.
The invention also relates to these kits where the therapeutic agent comprises at least one of camptothecin, taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to these kits where the therapeutic agent comprises methotrexate, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention also relates to these kits where the therapeutic agent comprises mitoxantrone, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention also relates to these kits wherein the at least one therapeutic agent is camptothecin, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof.
The invention also relates to these kits wherein the therapeutic agent is camptothecin. The invention also relates to these kits wherein the therapeutic agent is 9-nitro-20(S) camptothecin. The invention also relates to these kits wherein the therapeutic agent is 9-amino-20(S) camptothecin.
The invention also relates to these kits wherein the at least one therapeutic agent is taxol, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof.
The invention also relates to these kits where the stent is coated and the therapeutic agent is contained in the coating. The invention also relates to these kits where the therapeutic agent is contained within the stent structure. The invention also relates to these kits wherein the therapeutic agent is present in an amount effective to reduce cell proliferation once the stent is deployed. The invention also relates to these kits where the cell proliferation that is reduced is restenotic or cancerous. The invention also relates to these kits where the stent is biodegradable or is formed in situ.
In another aspect, the invention relates to an apparatus comprising an intraluminal catheter and a supply of at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells. The invention also relates to the apparatus comprising a container adaptable for connection to an intraluminal catheter, wherein the container contains at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells.
The invention also relates to the apparatus where the therapeutic agents comprise agents that interrupt cell replication and those that prevent or limit chemotaxis. The invention also relates to the apparatus where the therapeutic agent comprises at least one of camptothecin, taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to the apparatus where the therapeutic agent comprises methotrexate, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention also relates to the apparatus where the therapeutic agent comprises mitoxantrone, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to the apparatus wherein the at least one therapeutic agent is camptothecin, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. The invention also relates to the apparatus wherein the therapeutic agent is camptothecin. The invention also relates to the apparatus wherein the therapeutic agent is 9-nitro-20(S) camptothecin. The invention also relates to the apparatus wherein the therapeutic agent is 9-amino-20(S) camptothecin.
The invention also relates to the apparatus wherein the at least one therapeutic agent is taxol, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof.
The invention also relates to a method of treatment comprising administering at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells through an intraluminal catheter. The invention also relates to this method where the therapeutic agent comprises at least one of camptothecin, taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to this method where the therapeutic agent comprises methotrexate, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof. The invention also relates to this method where the therapeutic agent comprises mitoxantrone, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof.
The invention also relates to this method wherein the at least one therapeutic agent is camptothecin, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof. The invention also relates to this method wherein the therapeutic agent is camptothecin. The invention also relates to this method wherein the therapeutic agent is 9-nitro-20(S) camptothecin. The invention also relates to this method wherein the therapeutic agent is 9-amino-20(S) camptothecin.
The invention also relates to this method wherein the at least one therapeutic agent is taxol, its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof or functional equivalents thereof.
The invention also relates to this method where the method is used to treat restenosis, various types of cancers, insults to body tissue due to surgery, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.
The invention also relates to this method where the method is used to treat coronary, carotid, and cerebral restenotic lesions. The invention also relates to this method where the method is used to treat gliomas, other central nervous system tumors, tumors at localized sites including inoperable tumors, tumors where localized treatment of tumors would be beneficial, and solid tumors. The invention also relates to this method where the method is used to treat cell proliferation associated with joint surgery, bowel surgery, and cheloid scarring. The invention also relates to this method where the method is used to treat emphysema. The invention also relates to this method where the method is used to treat carpal tunnel syndrome. The invention also relates to this method where the method is used to treat disorders of tissues that are not highly vascularized.
The invention also relates to this method where the method is used to treat proliferative responses contributing to potential organ rejections or associated complications. The invention also relates to this method where the method is used to treat proliferative responses occurring as a result of transplantation of the heart, lung, liver, kidney, and other body organs or organ systems.
Further, this invention relates to a kit comprising a container adaptable for connection to an intraluminal catheter, wherein the container contains at least one therapeutic agent that is preferentially cytotoxic or cytostatic with regards to proliferating cells.
The inventor has unexpectedly discovered that uncontrolled cell proliferation can be controlled by administering therapeutic agents in a localized fashion, rather than systemically. Such localized administration allows for minimization of side effects as compared to systemic administration of the therapeutic agents. In the context of this invention, cell proliferation covers a broad range of uncontrolled cellular growth including, but not limited to chemotaxis and replication.
Specific cell proliferative indications that may be treated using this invention include restenosis, various types of cancers such as primary tumors, insults to body tissue due to surgery, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.
Specific types of restenotic lesions that can be treated using the present invention include coronary, carotid, and cerebral lesions. Specific types of cancers that can be treated using this invention include gliomas, other central nervous system tumors or tumors at localized sites including inoperable tumors or in tumors where localized treatment of tumors would be beneficial, and solid tumors. Treatment of cell proliferation due to insults to body tissue during surgery may be possible for a variety of surgical procedures, including joint surgery, bowel surgery, and cheloid scarring. Diseases that produce fibrotic tissue include emphysema. Repetitive motion disorders that may be treated using the present invention include carpal tunnel syndrome. An example of cell proliferative disorders that may be treated using the invention is a bone tumor.
The proliferative responses associated with organ transplantation that may be treated using this invention include those proliferative responses contributing to potential organ rejections or associated complications. Specifically, these proliferative responses may occur during transplantation of the heart, lung, liver, kidney, and other body organs or organ systems.
A number of therapeutic agents can be used in the practice of this invention. Among those are agents that interrupt cell replication and those that prevent or limit chemotaxis. Examples of suitable agents include those that interfere with cell mitosis and those that interfere with DNA synthesis. Particular agents that may be used in the practice of this invention include camptothecin (CPT), taxol, methotrexate, mitoxantrone, etoposide, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, rhizoxin, adriamycin and mitomycin, their physiologically tolerated salts, and derivatives, analogs, and conjugates thereof. Derivatives and analogs are defined to include prodrugs as well.
Any of the agents suitable for use in this invention may also be combined with other agents in a physiologically acceptable manner. This combination can peformed simultaneously (i.e. as a drug xe2x80x9ccocktailxe2x80x9d), sequentially, or a mixture of simultaneous and sequential therapies.
Two of therapeutic agents that may be used in this invention, CPT and taxol, are of particular interest.
Camptothecin is a plant alkaloid isolated from Camptotheca acuminata. While not wishing to be bound by any particular mechanism of action, the inventor believes that the following scientific information may be useful in understanding how camptothecin might achieve its effects. Studies on the mechanism of action of camptothecin and related compounds suggested that they may inhibit the enzyme topoisomerase I. Inhibition of this enzyme may result in inhibited DNA synthesis and may cause DNA strand breaks. Y-H. Hsiang et al., Cancer Res. 49:5077-5082 (1989). This document and all other documents specifically cited in this application are incorporated by reference as if reproduced in full herein.
It has also been suggested that the complex of DNA and topoisomerase I was stabilized by camptothecin, preventing reannealing of DNA, but still allowing the cleavage of the DNA strand. Id. Studies of camptothecin and its analogs suggested that only the compounds that inhibited topoisomerase I were active. In contrast, those analogs that did not inhibit topoisomerase I were inactive as inhibitors of cell proliferation in the L1210 cell line. Y-H Hsiang et al., Proc. Am. Assoc. Cancer Res. 30:622 (1989) (Abstract).
Overall, these activities suggest the underpinnings for cytotoxic and/or cytostatic effects with greater activity against proliferating cells than quiescent or normal cells. See also P. Pantazis et al., Complete inhibition of growth followed by death of human malignant melanoma cells in vitro and regression of human melanoma xenografts in immunodeficient mice induced by camptothecins, Cancer Res. 52:3980-3987 (1992); P. Pantazis et al., Regression of human breast carcinoma tumors in immunodeficient mice treated with 9-nitrocamptothecin: differential response of nontumorigenic and tumorigenic human breast cancer cells in vitro, Cancer Res. 53:1577-1582 (1993); P. Pantazis et al., Camptothecin derivatives induce regression of human ovarian non-tumorigenic and tumorigenic cells in vitro, Int. J. Cancer 53:863-871 (1993).
Chemical derivatives of CPT can be prepared either in a semisynthetic or totally synthetic way. (See, e.g., Wani, M. C. et al., J. Med. Chem. 23:544, 1980; Wani, M. C. et al., J. Med. Chem. 30:2317 (1987). Camptothecin Sodium Salt (CPT Na+), 9-Nitro-20(S)-Camptothecin (9NO2) and 9-Amino-20(S)-Camptothecin (9AC) can also be synthesized from CPT. CPT and derivatives thereof usually are extensively purified prior to administering for use in the present invention because: (1) the natural product contains several other components which have a large degree of toxicity, and (2) FDA regulations require such purifying for any drug or compound to be used as a medicine. Methods of purification known by those skilled in the art can be used, e.g.xe2x80x94dissolving the CPT in a suitable solvent such as chloroform or methylene chloride and then adsorbing onto a column containing silica gel and then carrying out elution of the adsorbed materials by increasing the polarity of the eluant by adding, e.g., methanol.
The purity of the compound can be tested by high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) and other appropriate methods known in the art. The compound can also be completely characterized using infrared (IR), ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy and elemental analysis.
Furthermore, the CPT and derivatives thereof used in the present invention are water-insoluble and not administered in the chemically and physically different sodium salt form. This difference can easily be observed by looking at their elemental analysis, NMR, UV and IR spectra and also by their different physical behavior in HPLC and TLC experiments.
The derivatives of CPT for use in the present invention include, for example, 9NO2-20(S) (aka 9NC), and 9AC-20(S). Other related derivatives may also be used in conjunction with the method of the present invention. Examples include dimethylaminomethyl-10-hydroxy-20(S)-CPT (topotecan), 7-ethyl-10-[4-(1-piperdino)-1-piperdino]-carbonyloxy-CPT (CPT-11), 7-ethyl-10-hydroxy-20(S)-CPT, 9-amino-CPT, 9-nitro-CPT, 10,11-methylenedioxy-20(S)-CPT, 9-chloro-20(S)-CPT, 9-bromo-20(S)-CPT, 9-hydroxy-20(S)-CPT, 11-hydroxy-20(S)CPT, and 10-hydroxy-20(S)-CPT. Additionally, the camptothecin derivatives disclosed in WO 97/28165 (Zhisong, et al.) may be used in the practice of this invention.
Use of taxol for systemic treatment of cancer has been reasonably extensive. While not wishing to be bound by any particular mechanism of action, the inventor believes that the following scientific information may be useful in understanding how taxol might achieve its effects. Studies on the mechanism of action of taxol and its derivatives suggest that it promotes microtubule formation from tubulin and stabilizes microtubules by preventing depolymerization. M. A. Jordan et al. Proc. Natl. Acad. Sci. USA, 90:9552-9556 (1993). This stabilization may interfere with the normal microtubule reorganization that is essential for cell division and may result in mitotic arrest of dividing cells. The may prevent cell division in proliferating cells. In many cell types, apoptosis and cytotoxic effects may also be demonstrated. These effects may lead to beneficial effects in diseases such as cancer or other cell proliferative diseases such as restenosis, where selective activity against proliferative versus normal cells has been suggested.
The side effect profiles of taxols administered systemically have been investigated previously. Brown et al., in xe2x80x9cA Phase I Trial of Taxol Given By A 6-Hour Intravenous Infusionxe2x80x9d J. of Clin. Oncol., Vol. 9, No. 7. pp. 1261-1267 (July, 1991) report on a Phase I Trial in which taxol was provided as a 6-hour IV infusion every 21 days without premedication. 31 patients received 64 assessable courses of taxol. One patient had a severe (or acute) hypersensitivity reaction, which required discontinuation of the infusion and immediate treatment to save the patients life. Another patient experienced a hypersensitivity reaction, but it was not so severe as to require discontinuing the infusion. Myelosuppression was dose-limiting, with 2 fatalities due to sepsis. Non-hematologic toxicity was of Grade 1 and 2, except for one patient with grade 3 mucositis and 2 patients with Grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias, requiring discontinuation of taxol in two patients. Four partial responses were seen (3 in patients with non-small-cell lung cancer, and one in a patient with adenocarcinoma of unknown primary). The maximum tolerated dose reported was 275 mg/m2, and the recommended Phase II starting dose was 225 mg/m2. The incidence of hypersensitivity reaction was reported to be schedule-dependent with 6 to 24-hour infusions of drug having a 0% to 8% incidence of hypersensitivity reactions. It was also reported that hypersensitivity reactions persist with or without premedication despite prolongation of infusion times. Since these Phase I studies were conducted on terminally ill patients suffering from a variety of cancers, the efficacy of the taxol treatments could not be determined.
In a study by Kris et al., taxol formulated with Cremaphor EL in dehydrated alcohol was given as a 3-hour IV infusion every 21 days, with the administered dosage ranging from 15 to 230 mg/m2 in nine escalation steps. Kris et al. concluded that xe2x80x9cwith the severity and unpredictability of the hypersensitivity reactions, further usage of taxol is not indicated with this drug formulation on this administration schedule.xe2x80x9d See Cancer Treat. Rep., Vol. 70, No. 5, May 1986.
Since early trials using a bolus injection or short (1-3 hour) infusions induced anaphylactic reactions or other hypersensitivity responses, further studies were carried out in which taxol was administered only after premedication with steroids (such as dexamethasone), antihistamines (such as diphenhydramine), and H2antagonists (such as cimetidine or ranitidine), and the infusion time was extended to 24 hours in an attempt to eliminate the most serious allergic reactions. Various Phase I and Phase II study results have been published utilizing 24-hour infusions of taxol with maximum total dosages of 250 mg/m2, generally with the course being repeated every 3 weeks. Patients were pretreated with dexamethasone, diphenhydramine, and cimetidine to offset allergic reactions. See Einzig, et al., xe2x80x9cPhase II Trial of Taxol in Patients with Metastatic Renal Cell Carcinoma.xe2x80x9d Cancer Investigation, 9(2) 133-136 (1991), and A. B. Miller et al., xe2x80x9cReporting Results of Cancer Treatment,xe2x80x9d Cancer, Vol. 47, 207-214 (1981).
Koeller et al., in xe2x80x9cA Phase I Pharmacokinetic Study of Taxol Given By a Prolonged Infusion Without Premedication.xe2x80x9d Proceedings of ASCO, Vol. 8 (March 1989), recommends routine premedication in order to avoid the significant number of allergic reactions believed to be caused by the cremaphor (polyethoxylated castor oil) vehicle used for taxol infusions. Patients received dosages ranging from 175 mg/m2 to 275 mg/M2.
Wiernik et al., in xe2x80x9cPhase I Clinical and Pharmacokinetic Study of Taxol.xe2x80x9d Cancer Research, 47, 2486-2493 (May 1, 1987), also report the administration of taxol in a cremaphor vehicle by IV infusion over a 6-hour period in a Phase I study. Grade 3-4 hypersensitivity reactions incurred in 4 of 13 courses. The starting dose for the study was 15 mg/m2 (one-third of the lowest toxic dose in dogs). Doses were escalated, and a minimum of 3 patients were treated at each dose level until toxicity was identified, and then 4-6 patients were treated at each subsequent level. The study concluded that neurotoxicity and leucopenia were dose-limiting, and the recommended Phase II trial dose was 250 mg/m2 with premeditation.
Other exemplary studies on taxol include: Legha et al., xe2x80x9cPhase II Trial of Taxol in Metastatic Melanoma.xe2x80x9d Vol. 65 (June 1990) pp. 2478-2481; Rowinsky et al., xe2x80x9cPhase I and Pharmacodynamic Study of Taxol in Refractory Acute Leukemias.xe2x80x9d Cancer Research, 49, 4640-4647 (Aug. 15, 1989); Grem et al., xe2x80x9cPhase I Study of Taxol Administered as a Short IV Infusion Daily for 5 Days,xe2x80x9d Cancer Treatment Reports, Vol. 71 No. 12 (December, 1987); Donehower et al., xe2x80x9cPhase I Trial of Taxol in Patients With Advanced Cancer,xe2x80x9d Cancer Treatment Reports, Vol. 71, No. 12, (December 1987); Holmes et al., xe2x80x9cPhase II Study of Taxol in Patients (PT) with Metastatic Breast Cancer (MBC).xe2x80x9d Proceedings of the American Society of Clinical Oncology, Vol. 10, (March, 1991), pp. 60. See also Suffness, xe2x80x9cDevelopment of Antitumor Natural Products at the National Cancer Institute.xe2x80x9d Grann Monograph or Cancer Research, 31 (1989) pp. 21-44 (which recommends that taxol only be given as a 24-hour infusion).
In addition to taxol, other forms such as its physiologically tolerated salts, and derivatives, analogs, mixtures and conjugates thereof may be used in the practice of this invention. Examples of derivatives or analogs of taxol are 2xe2x80x2 and 7 positions substituted taxols disclosed by A. E. Mathew, et al. Synthesis and evaluation of some water-soluble prodrugs and derivatives of taxol with antitumor activity, J. Med. Chem. 35:145-51 (1992). An example of taxol conjugates useful in the practice of this invention are disclosed in R. B. Greenwald, et al., Drug Delivery Systems: water soluble taxol 2xe2x80x2poly(ethylene glycol) ester prodrugs-design and in vivo effectiveness, J. Med. Chem. 39:424-31 (1996). Examples of derivatives or prodrugs of 2xe2x80x2 substituted taxol and camptothecin are disclosed in Peter D. Senter et al., The Role of Rat Serum Carboxylesterase in the Activation of Paclitaxel and Camptothecin Prodrugs, Cancer Research 56:1471-75 (1996). Additional examples of taxol prodrugs or derivatives can be found in G. I. Georg, et al., Synthesis of biologically active taxol analogs with modified phenylisoserine side chains, J. Med. Chem 35:4230-37 (1992); S. W. Mamber, et al., Tubulin polymerization by paclitaxel (taxol) phosphate prodrugs after metabolic activation with alkaline phosphatase, J. Pharmacol Exp. Ther. 274:877-83 (1995); S. Grover et al., Differential effects of paclitaxel (Taxol) modified at positions C-2, C-7, and C-3xe2x80x2 tubulin polymerization and polymer stabilization: identification of a hyperactive paclitaxel derivative, Biochemistry 34:3927-34 (1995).
Local delivery of inhibitory amounts of therapeutic agents for the treatment of cell proliferation can be by a variety of techniques and structures that administer the agents at or near the proliferative site. Examples of local delivery techniques and structures are not intended to be limiting but to be illustrative of the techniques and structures available. Examples include local delivery catheters, site specific carriers, implants, direct injection, or direct applications.
Local delivery by a catheter allows the administration of a therapeutic agent directly to the proliferative site. Examples of local delivery using a balloon catheter are described in EP 383 492 A2 and U.S. Pat. No. 4,636,195 to Wolinsky. Additional examples of local, catheter-based techniques and structures are disclosed in U.S. Pat. No. 5,049,132 to Shaffer et al. and U.S. Pat No. 5,286,254 to Shapland et al.
Generally, the catheter must be placed such that the therapeutic agent can be delivered at or near the proliferative site. Dosages delivered through the catheter can vary, according to determinations made by one of skill, but should be in amounts effective to create a cytotoxic or cytostatic effect at the proliferative site. Typically, these total amounts are less than the total amounts for systemic administration of the therapeutic agent. The therapeutic agents delivered through catheters typically should be formulated to a viscosity that enables delivery through a small treatment catheter, and should be formulated with pharmaceutically acceptable additional ingredients (active and inactive).
Local delivery by an implant describes the placement of a matrix that contains the therapeutic agent into the proliferative site. The implant may be deposited by surgery or other means. The implanted matrix releases the therapeutic agent by diffusion, chemical reaction, solvent activators, or other equivalent mechanisms. Examples are set forth in Lange, Science 249:1527-1533 (September, 1990). Often the implants may be in a form that releases the therapeutic agent over time; these implants are termed time-release implants. The material of construction for the implants will vary according to the nature of the implant and the specific use to which it will be put. For example, biostable implants may have a rigid or semi-rigid support structure, with therapeutic agent delivery taking place through a coating or a porous support structure. Other implants made be made of a liquid that stiffens after being implanted or may be made of a gel. The amounts of therapeutic agent or agents present in or on the implant may be in an amount effective to treat cell proliferation generally, or a specific proliferation indication, such as the indications discussed herein.
One example of local delivery of the therapeutic agent by an implant is use of a biostable or bioabsorbable plug or patch or similar geometry that can deliver the agent once place in or near the proliferative site. An example of such implants can be found in U.S. Pat. No. 5,429,634 to Narciso, Jr., incorporated by reference. A particular application of use of an implant according to the invention is treatment of cell proliferation in tissue that is not highly vascularized, as discussed briefly above. An example of such tissue is bone tissue. The difficulty in treating uncontrolled proliferative cell growth in bone tissue may be exemplified by the difficulties in treating bone tumors. Such tumors are typically refractory to treatment, in part because bone tissue is not highly vascularized. An implant in or near the proliferative site may potentially have localized cytotoxic or cytostatic effects with regard to the proliferative site. Therefore, in one embodiment, the invention may be used to treat bone tumors.
Another example of local delivery by an implant is the use of a stent. Stents are designed to mechanically prevent the collapse and reocclusion of the coronary arteries. Incorporating a therapeutic agent into the stent may deliver the agent directly to or near the proliferative site. Certain aspects of local delivery by such techniques and structures are described in Kohn, Pharmaceutical Technology (October, 1990), incorporated by reference. Stents may be coated with the therapeutic agent or agents to be delivered. Examples of such techniques and structures may be found in U.S. Pat. No. 5,464,650 to Berg et al., U.S. Pat. No. 5,545,208 to Wolff et al., U.S. Pat. No. 5,649,977 to Campbell, U.S. Pat. No. 5,679,400 to Tuch, EP 0 716 836 to Tartaglia et al., all of which are incorporated by reference. Alternatively, the therapeutic agent loaded stent may be biorotable, i.e. designed to dissolve, thus releasing the agent in or near the proliferative site, as disclosed in U.S. Pat. No. 5,527,337 to Stack et al., incorporated by reference. The present invention can be used with a wide variety of stent configurations, including, but not limited to shape memory alloy stents, expandable stents, and stents formed in situ.
Amounts of the therapeutic agent or agents delivered by the stent can vary, according to determinations made by one of skill, but should be in amounts effective to create a cytotoxic or cytostatic effect at the proliferative site. Typically, these total amounts are less than the total amounts for systemic administration of the therapeutic agent. Appropriate release times can vary, but preferably should last from about 1 hour to about 6 months, most preferably from about 1 week to about 4 weeks. Formulations including the therapeutic agent for delivery of the agent via the stent can vary, as determinable by one of skill, according to the particular situation, and as generally taught herein.
Another example is a delivery system in which a polymer that contains the therapeutic agent is injected into the proliferative cells in liquid form. The polymer then cures to form the implant in situ. One variation of this technique and structure is described in WO 90/03768 to Donn, incorporated by reference.
Another example is the delivery of a pharmaceutical agent by polymeric endoluminal sealing. This technique and structure uses a catheter to apply a polymeric implant to the interior surface of the lumen. The therapeutic agent incorporated into the biodegradable polymer implant is thereby released at the proliferative site. One example of this technique and structure is described in WO 90/01969 to Schindler, incorporated by reference.
Another example of local delivery by an implant is by direct injection of vesicles or microparticulates into the proliferative site. These microparticulates may comprise substances such as proteins, lipids, carbohydrates or synthetic polymers. These microparticulates have the therapeutic agent incorporated throughout the microparticle or over the microparticle as a coating. Examples of delivery systems incorporating microparticulates are described in Lange, Science, 249:1527-1533 (September, 1990) and Mathiowitz, et al., J. App. Poly Sci. 26:809 (1981), incorporated by reference.
Local delivery by site specific carriers describes attaching the therapeutic agent to a carrier which will direct the drug to the proliferative site. Examples of this delivery technique and structure include the use of carriers such as a protein ligand or a monoclonal antibody. Certain aspects of these techniques and structures are described in Lange, Science 249:1527-1533, incorporated by reference.
Local delivery also includes the use of topical applications. An example of a local delivery by topical application is applying the therapeutic agent directly to an arterial bypass graft during a surgical procedure. Other equivalent examples will no doubt occur to one of skill in the art.
Finally, there are other equivalent techniques and structures for delivering the therapeutic agent besides those techniques discussed above. Such techniques and structures will no doubt occur to one of ordinary skill, and are within the scope of this invention.


A surface mounted inductor is equipped with a coil formed by winding a conductive wire, and a formed body in which the coil is sealed with a sealing material that mainly contains metal magnetic powder and a resin. The coil is embedded so that surfaces of lead-out ends are exposed on surfaces of the formed body. The resin at portions of surfaces of the formed body where external terminals are formed is removed, and the metal magnetic powder and a plating layer forming the external terminals are joined to each other, thereby connecting the external terminals and the lead-out ends of the coil.

As a conventional surface mounted inductor, as shown in FIG. 5, there is a surface mounted inductor in which a conductive wire is wound to form a coil 21, the coil 21 is embedded in a formed body 22 formed with a sealing material that contains magnetic powder and a resin, and the coil 21 is connected to external terminals 24 formed on surfaces of the formed body 22 (for example, refer to JP 2010-245473 A). In this surface mounted inductor, the coil 21 formed by winding the conductive wire is placed on a tablet, the coil and the tablet are arranged in a molding die so that a lead-out end 21b of the coil 21, which is placed along an outer side surface of a pillar-shaped convex portions of the tablet, is interposed between the outer side surface of the pillar-shaped convex portions of the tablet and an inner wall surface of a molding die. Using this molding die, a formed body 22 incorporating the coil 21 is formed by a compression molding method or a powder compacting method. A conductive paste is applied to the formed body by dipping to form external terminals 24.
Recently, accompanying further miniaturization of electronic equipment, in the surface mounted inductor with such a structure, there is a possibility that an external electrode formed on an upper surface is brought into contact with a shielding plate and thereby short-circuited. Therefore, there has been an increased demand for a surface mounted inductor in which the electrode is formed to have an L-shaped structure.
Under such circumstances, in the conventional surface mounted inductor, when attempting to form an external terminal with an L-shaped structure, since the conductive paste is applied to the formed body by dipping, it was difficult to form the external terminal in an L-shape. Furthermore, in the conventional surface mounted inductor, since the formed body is dipped in the conductive paste stored in a conductive paste tank, the conductive paste in an amount enough to immerse portions forming external terminals of the formed body is required, and besides that, if the amount to be disposed of for the sake of quality control is included, a large amount of the conductive paste goes to waste resulting also in a cause of an increase in production cost.
In order to solve such problems, as shown in JP 2009-170488 A, an external terminal was formed with a plate-shaped metal frame, the overall shape is increased by a thickness of the metal frame, while the sizes of the coil and the formed body are reduced, so that the adequate characteristics cannot be obtained, and an increased number of man-hours is required to form the external terminal.
As an alternative solution, forming the external terminals by sputtering is considered, but expensive equipment is required.

Method for manufacturing a surface mounted inductor


A method performed by a User Equipment (UE) for managing sub-flow communications is provided, the method includes selecting a sub-flow among a plurality of sub-flows of the UE based on a set of parameters associated with each of the plurality of sub-flows, and transmitting a plurality of Transmission Control Protocol (TCP) acknowledgement messages in a single frame through the selected sub-flow, the plurality of TCP acknowledgement messages being associated with the plurality of sub-flows.

Multipath Transmission Control Protocol TCP (MPTCP) provides mechanism to receive and/or transmit data on multiple paths and/or sub-flows simultaneously or contemporaneously, with each path and/or sub-flow being assigned with one Internet Protocol (IP) address. Present mobile devices contain more than one communication entity (e.g., wireless communication method) such as cellular communication (2nd Generation (2G)/3rd Generation (3G)/Long-Term Evolution (LTE)) and/or WiFi. In order to utilize mobile device resources (e.g., power resources) efficiently and/or increase communication bandwidth, mobile devices contemporaneously establish connections with two IP addresses, one with cellular communication and other with WiFi (e.g., multiple paths and/or sub-flows), using MPTCP. Benefits of contemporaneous communication with two IP addresses using MPTCP include better resource utilization, higher throughput, and/or faster handovers in delay sensitive applications.
Upon establishment of multiple sub-flows by a mobile device, downlink data packets are received on (e.g., over) each of the sub-flows. The mobile device transmits a Transmission Control Protocol (TCP) acknowledgement (ack) message in response to receiving each of such downlink data packets. The TCP ack message transmitted in response to a particular downlink data packet is transmitted over the same sub-flow over which the particular downlink data packet was received. Thus, as may be understood, time scheduling and/or transmitter arbitration is performed at the mobile device to coordinate the TCP ack transmissions over the different sub-flows. It is only after the transmission of such TCP ack messages, that subsequent downlink data packets are received. As a result, the downlink throughput associated with the different sub-flows may be reduced if the time scheduling and/or transmitter arbitration of the TCP ack messages is inefficient.
Thus, a solution that overcomes the above deficiencies would be desirable.

Managing sub-flow communications in user equipment


Methods and electronic circuits for executing instructions in a central processing unit (CPU) are provided. One of the methods includes forming an instruction block by sequentially fetching, from a current thread queue, one or more instructions including one jump instruction, wherein the jump instruction is the last instruction in the instruction block; transmitting the instruction block to a CPU execution unit for execution; replenishing the current thread queue with at least one instruction to form a thread queue to be executed; determining a target instruction of the jump instruction according to an execution result of the CPU execution unit; determining whether the target instruction is contained in the thread queue to be executed; and if not, flushing the thread queue to be executed, obtaining the target instruction and adding the target instruction to the thread queue to be executed.

In the contemporary big data cloud environment, the storage and processing of massive data are necessary, imposing higher requirements on how fast data is computed. It is well known that CPU performance is one determinant factor of computation speed. In order to enable faster computation, CPU is being constantly improved in various aspects, from physical process to logical control.
For example, to improve parallel processing power, the CPU hyper-threading technology has been proposed, in which hardware instructions of special characters are utilized to simulate a physical chip from two logical cores. In this way, a single processor is capable of thread-level parallel computation and thus compatible with multithreading parallel computation. In other words, a hyper-threaded CPU can run two or more threads in parallel on a single physical core, increasing the number of parallelizable instructions and exhibiting improved overall operating performance.
On the other hand, instruction prediction schemes are used to perform pre-fetching and pre-execution of instructions, to utilize a CPU's clock cycles more efficiently and avoiding pipeline bubbles or stalls.
These schemes have improved CPU execution efficiency to a certain extent. However, instruction prediction is not always accurate, and prediction misses can significantly deteriorate CPU execution efficiency.
Therefore, further improvements are desired to achieve higher CPU efficiency.

Method for replenishing a thread queue with a target instruction of a jump instruction


An image coding method includes: writing, into a coded bitstream, buffer description defining information for defining a buffer description; constructing a default reference list; reorder pictures included in the default reference list; writing, into the coded bitstream, reference list reordering information for indicating details of the reordering; and coding an image using the buffer description and a reference list resulting from the reordering, and in the reference list reordering information, among the pictures, a picture to be reordered is specified using an index which is used in other processing in the image coding method.

State-of-the-art video coding schemes, such as MPEG-4AVC/H.264 (see Non Patent Literature 1) and the upcoming HEVC (High-Efficiency Video Coding), perform coding of image or video content using inter-picture prediction from previously coded or decoded reference pictures. In other words, the video coding schemes exploit the information redundancy across consecutive pictures in time. In MPEG-4 AVC video coding scheme, reference pictures in the decoded picture buffer (DPB) are managed either using a predefined sliding-window scheme for removing earlier pictures in coding order from the DPB, or explicitly using a number of buffer management signals in the coded bitstream to manage and remove unused reference pictures.

Image coding method including reference list reordering information for indicating details of reordering pictures included in a reference list


An electric drive pump system includes a power end and a detachable transmission assembly. The transmission assembly is mounted to the power end and is configured to provide rotational power to the power end through a plurality of electric motors. The plurality of electric motors use a gearbox to drive an output spline that engages the power end. A control module is used to regulate the performance characteristics of the plurality of electric motors. A temperature regulation assembly is configured to regulate the temperature of the transmission assembly and the power end.

It is difficult to economically produce hydrocarbons from low permeability reservoir rocks. Oil and gas production rates are often boosted by hydraulic fracturing, a technique that increases rock permeability by opening channels through which hydrocarbons can flow to recovery wells. Hydraulic fracturing has been used for decades to stimulate production from conventional oil and gas wells. The practice consists of pumping fluid into a wellbore at high pressure (sometimes as high as 50,000 PSI). Inside the wellbore, large quantities of proppants are carried in suspension by the fracture fluid into the fractures. When the fluid enters the formation, it fractures, or creates fissures, in the formation. Water, as well as other fluids, and some solid proppants, are then pumped into the fissures to stimulate the release of oil and gas from the formation. When the pressure is released, the fractures partially close on the proppants, leaving channels for oil and gas to flow.
Fracturing rock in a formation requires that the fracture fluid be pumped into the well bore at very high pressure. This pumping is typically performed by large diesel-powered pumps in communication with one or more fluid ends. These specialized pumps are used to power the operation of the fluid end to deliver fracture fluids at sufficiently high rates and pressures to complete a hydraulic fracturing procedure or "frac job." Such pumps are able to pump fracturing fluid into a well bore at a high enough pressure to crack the formation, but they also have drawbacks. For example, the diesel pumps are very heavy, and thus must be moved on heavy duty trailers making transport of the pumps between oilfield sites expensive and inefficient. In addition, the diesel engines required to drive the pumps require a relatively high level of expensive maintenance. Furthermore, the cost of diesel fuel is much higher than in the past, meaning that the cost of running the pumps has increased.
To avoid the disadvantages of diesel-powered pumps, some have moved to another option, such as electrically powered pumps. The electric frac pump configurations available now are largely comprised of existing mechanical units that are integrated into an electric system. This practice, however, can limit an operation's efficiency and performance.
Operators have at least two alternatives to choose from when in pursuit of a clean, electric power end pump. The first option offers a dual-motor configuration coupled with up to two triplex pumps. This large, industrial-sized, and air-cooled system can be capable of 3600-4500 hydraulic horsepower (HHP). The second option is a single-motor configuration. The centrally located motor is connected by two quintuplex pumps via a through-spindle design. This larger unit is also air-cooled, and is capable of 6000 HHP. Existing electric configurations experience inefficiencies in certain key areas. Contemporary offerings for electric frac configurations are composed of existing components from mechanical systems that are repurposed for electric applications. These components were not specifically built for electric systems. Consequently, effective horsepower is decreased due to design conflicts introducing hydraulic and mechanical resistance, as well as accelerated wear cycles as a result of violent harmonics and misalignments in provisional electric systems.
The inefficiencies do not end there: air-cooling solutions often leave something to be desired, as they are not capable of regulating the temperatures the motors generate, especially in environments where heat is a special concern. This leads to motors running hotter, and therefore, far less efficiently, which reduces the effective hydraulic horsepower of the entire operation. The inability to regulate running temperatures can also lead to premature failure.
There are other concerns regarding the integration of existing mechanical components and electrics, such as the optimization of the ratios used by power end reduction gears. Electric motors are often mistakenly considered to produce the same results at any RPM. Even though they have flatter and more consistent torque and power curves than internal combustion solutions, this is not entirely true. Electric motors do perform best within a certain RPM range, and contemporary offerings have not taken full advantage of the optimization that understanding provides. Reduction gear ratios that were not chosen for use in a specific electrical application, expose motors that drive them to possible premature failure, whether it be from spinning outside of the optimal range, or introducing harmonic imbalances and damaging the powertrain as a whole.
Although great strides have been made with respect to the power end of a fracturing pump system, there clearly is room left for improvement in electric drive pump fracing systems.

Electric drive pump for well stimulation


The invention is a communication management module for effectively controlling an optical interface that uses a control panel indicator in an appliance for communication. The module includes a physical, framing, transport, dispatch, and application layers. The module is implemented to verify the integrity of data frames and to correlate data frames and responses with applications in the application layer.

Appliance devices such as dishwashers, clothes washing machines, dryers, ovens, refrigerators and the like often comprised of electromechanical components. Some of these components have knobs or selector switches so a user may control operational parameters of the appliance. In many cases, the overall operation of the appliance is predefined as a general matter and the settings or selections input by a user merely modify the predefined operation in some way.
For example, the operation of a dishwasher typically involves the processes of filling, washing, draining and rinsing. Such operations involve, among other things, the control of water valves, drain valves and motor relays. The general sequence of such operations is generally predefined. However, user input may be used to alter the sequence of operations within a cycle or to define certain parameters for the entire sequence or parameters within an operation of the sequence. For example, the user input may define whether the wash cycle is normal, light, or heavy. Parameters within an operation of sequence include the temperature of the wash or rinse cycle. Although the general sequence of the overall cycle does not necessarily change dependent upon wash cycle selection, the length or parameters of certain operations within the cycle sequence may change.
A typical user input interface for an electromechanical appliance may include a rotary knob and a plurality of pushbutton switches. The rotary knob may be attached to a mechanical timer having a cam that controls the sequence of operations within the appliance. The cam has a number of followers that trigger the operation of the various appliance components. The cam followers are positioned to cause various operations to be executed in a "programmed" sequence. The user selects a particular cycle by rotating the knob to a particular position associated with the selected cycle. Upon actuation, the cam begins to rotate automatically started from the user selected position to trigger each operation as defined on the cam "program" from the user-selected point forward. The pushbutton switches are used to activate/deactivate various options that are not available through the cam activated program. For example, pushbutton switches may be used to selectively activate such features as a heated dry cycle, a delayed start, or a high temperature wash in a dishwasher, for example.
More recently, electronic controllers, for example, microprocessors and microcontrollers, have replaced the rotary cam control device. The use of electronic controllers provides flexibility and features not typically available in cam control devices. Moreover, as a general matter, replacement of moving parts, such as electromechanical rotating cams, typically increases reliability in products. One aspect of electromechanical appliances not available in appliances with electronic controllers is an indication of the operation in a cycle sequence being performed. In electromechanical appliances, the knob by which the cam was set typically included an arrow or other pointer that pointed towards indicia on the control panel adjacent the knob. By looking at the position of the knob and the indicia to which it pointed, the user could ascertain the operation being performed by the appliance.
To provide an indication of the operation being performed, many appliances having electronic controllers also include indicators such as small electrical lights or light emitting diodes (LEDs). These indicators are typically located adjacent indicia on an appliance control panel. As the electronic controller deactivates one operation and activates another, the controller also operates one or more switches to turn off the indicator beside indicia identifying the operation being deactivated and turning on the indicator beside indicia identifying the operation being activated. In this manner, the user is provided visual feedback regarding the current operational state of the appliance.
The use of electronic controllers has added to the complexity of servicing appliances. Small electronic integrated circuits do not lend themselves to the methods of troubleshooting and repair that have historically been used with mechanical and electromechanical devices. Accordingly, malfunctions in an electronically controlled appliance are more difficult to diagnose and resolve than those of the old, mechanical cam controlled devices.
Some have proposed the incorporation of infrared and radio communication devices in appliances having microprocessors for the purpose of communicating troubleshooting data. However, infrared and radio communication modules add appreciable expense to the manufacture of appliances. Because appliance manufacturers operate with relatively low profit margins, an increase of even one dollar in cost is multiplied by the production output, which may be in the millions of units. Thus, the additional expense of long range communication modules, such as infrared and radio communication devices, may significantly impact the bottom line of an appliance manufacturer.
In an effort to provide a low cost communication interface for an appliance having an electronic controller, the assignee of the present invention has developed an optical communication interface that effectively uses the indicators of the appliance for communication. This optical communication interface is the subject of pending U.S. patent applications bearing Ser. Nos., 10/264,888 filed Oct. 4, 2002, and 10/348,305 filed Jan. 21, 2003, that are entitled "Appliance Control Communication Methods and Apparatus," and "System and Method for Communicating with an Appliance Through a Light Emitting Diode," respectively. These applications are hereby expressly incorporated by reference. As set forth in these applications, an electronic controller may control the on/off status of an indicator to provide a digital optical signal that may be received by an externally located phototransistor or other LED. The digital signal from the appliance may be used to provide data from the appliance to external data storage for analysis or transmission. Additionally, an external device may transmit a signal to the appliance in a reverse manner because a LED used as an indicator on an appliance may respond as a phototransistor to light and generate a corresponding electrical signal. This signal may be received by the electronic controller and used to modify data or program control within the appliance.
While the optical interface may support communication with an electronic controller so data may be exchanged with an appliance, data communication problems also arise in the management of the interface and the communication received through it. One problem that arises regards the amount of resources to allocate to the management of the communication interface. In most electronic controllers used in appliances, program and data memory space are typically at a premium. Consequently, communication management of the interface needs to be efficient. Another problem with management of the interface in an appliance is the validity of the data. That is, the controller and the external device need to determine whether data received is the data that was transmitted. Furthermore, the electronic controller needs to be able to determine whether all data elements of a data message have been received.
While network protocols are available that provide data message verification and that assess whether complete messages have been received, such protocols and programs that implement them are not good candidates for optical interface control in an appliance. For one, they require a lot of memory resources. For another, they assume the coupling of a device to a network with each device having an unique identifier. The processing of the identifier and forwarding of messages not addressed to the recipient requires overhead processing and resources that may not be available in an appliance.
Consequently, there is a need for communication management in an appliance without significantly increasing the costs of manufacturing an appliance.
There is a need for communication management that does not require a fully orbed network communication controller and program.

System and method for communicating with an appliance through an optical interface using a control panel indicator


The present invention relates to a non-aqueous electrolyte for a lithium secondary battery and a lithium secondary battery comprising the same, the non-aqueous electrolyte comprising a non-aqueous organic solvent, a lithium salt, a first additive including at least one of compounds represented by chemical formulas 1 to 4, and a second additive comprising a cyclic sulfide-based compound, wherein the mixing ratio of the first additive and the second additive is a weight ratio of 0.2:1 to 10:1.

Technology development for realizing high capacity of a lithium secondary battery has been continuously made due to an increasing demand on a mobile equipment or a portable battery.
As for a positive active material of a lithium secondary battery, a lithium-transition metal oxide having a structure capable of intercalating lithium ions such as LiCoO2, LiMn2O4, LiNi1-xCoxO2 (0<x<1), and the like has been used.
As for a negative active material for a lithium secondary battery, various carbon-based materials including artificial graphite, natural graphite, and hard carbon capable of intercalating and deintercalating lithium ions have been used.
As an electrolyte of a lithium secondary battery, a lithium salt dissolved in an organic solvent has been used.

Non-aqueous electrolyte for lithium secondary battery and lithium secondary battery comprising same


An image scanner of the present invention includes an angle sensor for controlling subscanning and implemented by a position sensitive light detector (PSD). The angle sensor allows a subscanning mirror to be rotated at high speed without any vibration. A slit plate for causing a restricted part of light issuing from a light emitting element to be incident to the PSD is so configured as to cover the light emitting element, thereby reducing the size of the image scanner.

The present invention relates to an image scanner for transforming a text image or a graphic image to corresponding digital data and, more particularly, to an image scanner for reading partial images with a linear image sensor and combining them by subscanning to thereby output a complete bidimensional image.
A camera type image scanner having a reading unit including a liner image sensor and a subscanning mechanism is conventional. This type of image sensor reads a document while being spaced from the document. An image scanner DS-3000 available from Chinon Industries Inc. is one of such image scanners. Specifically, the image scanner includes a subscanning mirror rotated by the combination of a stepping motor and a decelerator, thereby sequentially varying the image to be projected onto the linear image sensor. The prerequisite with this type of image scanner is that the stepping rate of the stepping motor be increased with a decrease in required reading time. However, it is difficult to drive stepping motors in general at speeds higher than 1,000 ppm (pulses per minute). Further, vibration ascribable to the operation of the stepping motor has adverse influence on the mirror and other constituents of the image scanner, introducing irregularity in the resulting image. Moreover, gears of utmost accuracy are essential because the image is expanded or contracted unless the decelerator is free from eccentricity.
Japanese Patent Laid-Open Publication No. 1-265663, for example, teaches an image inputing device including a scanning section capable of controlling the rotation angle of a movable mirror. The image inputing device is capable of reducing the irregularity of the output of a photoelectric transducer to a negligible degree. Specifically, the mirror reflects light incident thereto from a subject. A focusing unit focuses the resulting reflection from the mirror onto an image pick-up surface where photoelectric transduction elements are arranged in an array. The transduction elements convert the incident light to an electric signal by main scanning. Every time main scanning completes once, the mirror is angularly moved in the subscanning direction such that the next part of the image is incident to the transduction elements. The problem with the image inputing device is that it lacks means for sensing the rotation angle of the mirror and therefore needs a stepping motor and a deceleration mechanism for controlling the movement of the mirror. This also lowers image quality in the event of high-speed reeding.
Japanese Patent Laid-Open Publication No. 8-7073 also proposes an image scanner of the type controlling the rotation angle of the subscanning mirror by sensing it. The image scanner taught in this document is feasible for high-speed drive. However, this image scanner needs an optical pickup, or sensor, consisting of a number of parts including a laser, light-sensitive element, objective lens, half-mirror, and VCM (Voice Coil Motor) for lens focusing. This makes it difficult to miniaturize the optical pick-up and therefore the entire reading unit. Further, two feedback control lines, one for lens focusing and the other for the rotation of the mirror, are required, rendering circuitry and adjustment sophisticated. Moreover, high-speed operation would cause the mechanical portions to vibrate and would thereby lower image quality. In addition, such an image scanner needs a great number of parts which would increase the cost.
Technologies relating to the present invention are also disclosed in, e.g., Japanese Patent Laid-Open Publication No. 60-128775, Japanese Utility Model Laid-Open Publication No. 62-151268, and Japanese Patent Laid-Open Publication No. 8-154153.


A protector with a sensor couples to a sliding door. A first end of an insert made of a non-conductive material is inserted in and fills up a space on a hollow part of the protector, and a terminal part is into die molding. The insert includes at least two feeding ports to receive and feed molding material into the insert during die molding. The feeding ports are spaced from each other and formed along a direction in which a wire harness extends. Covered parts are exposed from the wire harness where the covered parts are faced with the feeding ports.

The present invention relates to a protector with a sensor. When an object including a finger is disposed between an opening of an automobile body and a panel which moves between at least two positions to open and close the opening of the automobile body, the sensor fixed in the protector outputs a corresponding signal upon detecting the object. The panel includes doors such as a sliding door, a back door, and a sun roof, on a wagon, a station wagon, or the like.
A protector 10, 20 with a sensor couples to an automobile including a wagon illustrated in FIG. 10 and an automobile illustrated in FIG. 11. A sliding door 1 (or a back door) of the wagon opens and closes the opening of the automobile body. A sun roof 2 of the automobile opens and closes the opening of the automobile body.
The protector 10 couples to a front end surface of the sliding door 1 and extends toward a front part of the automobile body from the front end surface. The protector 10 extends in an upper and lower direction of the automobile body as illustrated in FIG. 12.
As illustrated in FIG. 13 and FIG. 14, the protector 10, which couples to the front end surface of the sliding door 1, includes an installation base member 11 and a hollow part 12. The installation base member 11 has a substantially U-shaped cross section including an inner-cabin side wall 11a, an outer-cabin side wall 11b, and a connecting wall 11c. The hollow part 12 is integrally formed with the installation base member 11. The hollow part 12 includes a sensor (pressure sensitive sensor) S. The sensor S outputs a corresponding electric signal upon detecting the object such as part of human bodies (fingers, hands, or legs) between the sliding door 1 and the opening of the automobile body (may also be front door or side door) (see, for example, Japanese Patent No. 3291233).
In a lower part of the protector 10, a channel part 13 is integrally formed with the inner-cabin side wall 11a of the installation base member 11. The channel part 13 has a substantially C-shaped cross section and holds a wire harness W. The wire harness W is joined with the pressure sensitive sensor S. The installation base member 11 has a plurality of holding lips 14, 14 formed inside and a core 15 embedded. The core 15 has a substantially U-shaped cross section and increases rigidity of the installation base member 11. In addition, a decorative lip 16 is provided on the outer-cabin side wall 11b of the installation base member 11.
The sensor (pressure sensitive sensor) S is fixed in the hollow part 12. The hollow part 12 has two core wires (electrode wires) 31, 32, rubber like elastic bodies 34, 35, and a space 33. The core wires 31, 32 extend in an upper and lower direction (longitudinal direction) and are embedded in the rubber like elastic bodies 34, 35. The rubber like elastic bodies 34, 35 have conductivity. The space 33 is positioned between the rubber like elastic bodies 34, 35. When the object is disposed between the sliding door 1 and the opening as the sliding door 1 is moved towards a closed position and the object makes contact with part of the hollow part 12, the object causes the rubber like elastic bodies 34, 35 to contact with each other and the two core wires 31, 32 to short. Resultant change in electric signal is transmitted to a control unit 40 by leads 36, 36, and as a result, the object is detected. The leads 36, 36 are connected with the two core wires 31, 32 in a lower side terminal part of the protector 10 and are joined with the control unit 40. The leads 36, 36 are covered with insulator and are tied by the wire harness W. Top ends of the leads 36, 36 are bared from covered parts 37, 37 and are naked wires.
As illustrated in FIGS. 15(a) to 15(c), in the lower side terminal part of the protector 10, the leads 36, 36 are piled on the two core wires 31, 32 and the leads 36, 36 are connected by means of resistance welding or soft soldering (FIG. 15(b)). The two core wires 31, 32 are drawn out in a longitudinal direction. Also, an insert 25 fills up the space 33 for the space 33 is exposed in an end part (FIG. 15(c)). Then, wire connection parts M1, the insert 25, and part of the wire harness W are embedded in a part molded by mold as illustrated in FIG. 16, and are not exposed. The insert 25 fills up the space 33 to prevent molding material from flowing into the space 33 and to prevent damages on sensing function. In FIG. 16, dotted lines indicate the part molded by mold.
Injection molding pressure affects the wire connection parts M1, embedded in the part molded by mold. In this connection, in the lower side terminal part of the protector 10, the wire connection parts M1 and the leads 36, 36 are firmly fixed to a surface of the insert 25 by adhesive for positioning. With this configuration, the wire connection parts M1 are not exposed from the part molded by mold or the wires are not damaged.
This configuration, however, necessitates an extra process of adhesion. In addition, an increased amount of adhesive causes insufficient adhesion. Also, use of adhesive tends to cause unevenness and makes it difficult to stably fix the wire connection parts M1. Further, the wire connection parts M1, once fixed to the surface of the insert 25 by adhesive, are hard to detach for repairment or replacement.
In case the leads 36, 36 are unevenly connected with the two core wires 31, 32, ends of the leads 36, 36 may stick out of the surface of the terminal part.
Japanese Patent No. 3291233 is directed to a metal piece as a clip to fix a connection part between cords. This configuration, however, is time-consuming and is complex, for the metal piece necessitates fixing by welding. In addition, Japanese Patent No. 3291233 does not disclose the insert or aim at preventing the molding material from flowing into the hollow part.
In this connection, FIG. 17 illustrates the protector 10. A first end of the insert 50 includes an insertion part 51, and a second end of the insert 50 includes a protrusion part 52 and a pressing part 54. The protrusion part 52 includes a support member 52A and a lid 52B to cover the support member 52A. The insertion part 51 is inserted in the space 33 to fill up the space 33. Wire connection parts M2 are sandwiched in and fixed by the support member 52A and the lid 52B. The wire connection parts M2 are where top ends of the leads 36, 36 are piled on top ends of the two core wires 31, 32. The pressing part 54 locally abuts with the wire connection parts M2. The terminal part is into die molding (see Japanese unexamined Patent Publication No. 2015-20548).
Accordingly, in the lower side terminal part of the protector 10, the support member 52A and the lid 52B on the second end of the insert 50, the covered parts 37, 37, and the part of the wire harness W are embedded in the part molded by mold and are not exposed.
The insertion part 51 prevents the molding material from flowing into the space 33. Also, the top ends of the leads 36, 36 and the top ends of the two core wires 31, 32 are electrically connected by the support member 52A and the lid 52B, which covers the support member 52A, not bonded directly. This configuration eliminates the need for use of adhesive or wire connection by resistance welding or soft soldering.
Also, with this configuration, exposure of the wire connection parts M2 from the part molded by mold or the damage on the wire connection parts M2 due to the injection molding pressure is prevented during die molding. The wire connection parts M2 are where the top ends of the leads 36, 36 are piled on the top ends of the two core wires 31, 32.
Unfortunately, however, while molding the lower side terminal part of the protector 10 by mold, illustrated in FIG. 17, air may be propagated along the covered parts 37, 37 or the wire harness W.
In case the air remains in the part molded by mold, the molding material is decreased in close adherence. The decreased close adherence leads to decreased water cut off function.
In this connection, Japanese Patent No. 6258735 is directed to a protector having a primary sealing layer and a secondary sealing layer. The primary sealing layer and the secondary sealing layer are formed by die molding and the secondary sealing layer is piled on the primary sealing layer. The protector, however, necessitates high manufacturing cost.
Therefore, an object of the present invention is to provide the protector stably formed by die molding and improved in the water cut off function.


A subject is placed in a more natural state or is encouraged to blink at specified intervals to obtain a measurement result under a fixed condition, and the judgment of the degree of dry eye is facilitated. A measurement part obtains, based on a reflected light flux from a subject eye, optical characteristic data of a two-dimensional vector form representing the time course of each optical characteristic of the subject eye in an blink interval from a certain blink to a next blink with respect to the first to the nth blink intervals. An analysis part one-dimensionally arranges each of the optical characteristic data with respect to the first to the nth blink intervals measured by the measurement part, and arranges the one-dimensional arrangement of the optical characteristic in a p-th blink interval at a p column to create a two-dimensional array, and performs a principal component analysis processing on the two-dimensional array.

1. Field of the Invention
The present invention relates to an ophthalmologic measuring apparatus, and particularly to an ophthalmologic measuring apparatus which performs a principal component analysis of ocular characteristic components changing by blinking, and facilitates judgment on the state of an eye, such as dry eye. In an embodiment of the invention, ocular characteristic components are obtained especially as optical characteristic components such as Zernike polynomials, optical characteristic data obtained plural times in an interval from the start point of timing when a blink starts to a point when a next blink starts are arranged longitudinally, and principal component processing is performed on the longitudinally arranged data.
2. Background Art
Hitherto, as an ophthalmologic measuring apparatus relating to dry eye, following techniques can be mentioned.
Patent document 1 discloses an ophthalmologic measuring apparatus which quantitatively measures fluorescence intensity from a cornea and tear fluid of a subject eye to which a specified fluorescence agent is applied. Patent document 2 discloses an ophthalmologic measuring apparatus which observes a color image of an interference pattern due to interference of reflected light between the front surface and back surface of a lipid layer, so that the state of the lipid layer of the subject eye, the state of flow of tear fluid and the like can be known, and a simple diagnosis of a local dry eye can be easily performed in a non-contact manner. Patent document 3 discloses an ophthalmologic tear observation apparatus in which only a signal light reflected from a tear film of a subject eye is made incident on a CCD, so that shading does not occur in an observation field, and a clear tear interference pattern without disturbance light can be observed in a wide observation field.
Patent document 4 discloses an ophthalmologic apparatus in which a subject is encouraged to blink at specified intervals while he/she is in a more natural state, a measurement result under a fixed condition is obtained, and a change with the passage of time for each individual or comparison of measurement results between different persons can be made more meaningfully.
Further, with respect to the principal component analysis, although non-patent document 1 discloses the application of the principal component analysis to the analysis of a time change in human eye wavefront aberration, the possibility of its usability is merely suggested, and a specific configuration is not clarified.
Patent document 1: JP-A-6-277179
Patent document 2: JP-A-7-136120
Patent document 3: JP-A-8-52112
Patent document 4: JP-A-2005-230328
Non-Patent document 1: "41st The Japanese Society of Ophthalmological Optics, 20th Ophthalmologic ME Society, Joint Society General Meeting, Abstracting Journal", Sep. 3, 2005, page 42
However, in the related art, merely the time change of the ocular aberration is seen, and as the ophthalmologic measuring apparatus used for the clinic of dry eye, it can not be said that demands relating to the judgment of the state of dry eye are sufficiently satisfied.