text
stringlengths 0
1.67M
|
|---|
1. A layered structure, said layered structure comprising a plastic substrate, at least one intermediate metallic layer on top of said plastic substrate and a metal or metal alloy layer on top of said intermediate metallic layer, characterised in that said metal or metal alloy layer comprises a solidified layer applied from the melt of a metal or metal alloy. 2. A layered structure according to claim 1, whereby said metal or metal alloy is applied by hot dip. 3. A layered structure according to claim 1, whereby said metal or metal alloy is selected from the group consisting of tin or tin alloys and zinc or zinc alloys. 4. A layered structure according to claim 1, whereby said metal or metal alloy layer has a thickness between 1 and 20 μm. 5. A layered structure according to claim 1, whereby said metal or metal alloy layer has at its surface a grain size of at least 5 μm. 6. A layered structure according to claim 1, whereby said plastic substrate comprises a thermoplastic material. 7. A layered structure according to claim 1, whereby said plastic substrate has a thickness between 10 and 500 μm. 8. A layered structure according to claim 1, whereby said plastic substrate is an elongated plastic substrate. 9. A layered structure according to claim 1, whereby said intermediate metallic layer has a melting point higher than 500° C. 10. A layered structure according to claim 1, whereby said intermediate metallic layer comprises nickel, copper, aluminium, cobalt or chrome or an alloy of one of these metals. 11. A layered structure according to claim 1, whereby said intermediate metallic layer has a thickness between 0.025 and 2 μm. 12. A layered structure according to claim 1, whereby an alloy layer is formed at the interface of said intermediate metallic layer and said metal or metal alloy layer. 13. A layered structure according to claim 1, whereby said layered structure comprises two intermediate metallic layers, the first intermediate metallic layer comprising a nickel layer and the second intermediate metallic layer comprising a copper layer. 14. A layered structure according to claim 1, whereby said layered structure is three-dimensionally deformed. 15. A method of manufacturing a layered structure, said method comprising the steps of providing a plastic substrate; applying at least one intermediate metallic layer on said plastic substrate; applying a metal or metal alloy layer on said intermediate metallic layer from the melt of a metal or a metal alloy and solidifying said metal or metal alloy layer. 16. A method of manufacturing a layered structure, said method comprising the steps of providing a plastic substrate; applying a first intermediate metallic layer on said plastic substrate; said first intermediate metallic layer comprising nickel; applying a second intermediate metallic layer on said first intermediate metallic layer; said second intermediate metallic layer comprising copper; applying a metal or metal alloy layer on said second intermediate metallic layer from the melt of a metal or a metal alloy and solidifying said metal or metal alloy layer. 17. A method according to claim 15, whereby said metal or metal alloy layer is applied by hot dip. 18. A method according to claim 15, whereby said intermediate metallic layer or layers is/are applied by chemical plating, electroplating, spraying, evaporation, chemical vapour deposition or sputtering. 19. A method of manufacturing a shielding material, said method comprises the step of deforming a layered structure according to claim 1 and/or the step of placing said layered structure in an injection mould and injection-moulding a plastic material in the mould. 20. A method according to claim 19, whereby said deforming comprises deep-drawing or thermoforming. 21. A shielding material obtainable by applying a method according to claim 19. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Metallized plastic substrates have found applications in the shielding of interfering radiation such as electromagnetic interfering (EMI) radiation of for example electronic equipment. Shielding is used either to protect an electronic equipment against external interfering radiation or to protect the environment from radiation generated by the electronic equipment itself. Several techniques to metallize a plastic substrate are known in the art. Such techniques comprise for example the application of a conductive paint or the application of a coating by chemical processes such as immersion plating or electroless plating, electroplating, chemical vapour deposition, vacuum evaporation or sputtering. Most of these coating techniques result in an expensive and complicated process. Therefore, regarding the increasing need for metallized substrates, there is still a big demand for a simple and cheap method to produce metallized substrates. Since the metallized substrate has to be formed into an object sized and shaped to enclose an electronic equipment, the metallized substrate shall have a high deformability. WO 99/40770 describes a method of fabricating a support provided with shielding characteristics against interfering radiation. A tin layer is electrolytically applied on a plastic substrate. The thus obtained metallized plastic is placed in an injection mould and plastic is injected into the mould to form the support. A drawback of the articles obtained by this method is their high cost since the application of a metal coating by electrolysis is an expensive process. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention to avoid the drawbacks of the prior art. It is another object of the invention to provide a layered structure with good shielding properties that can easily be deformed without deteriorating the shielding characteristics. It is also an object of the invention to provide a method to manufacture layered structures at low costs. Futhermore, it is an object of the invention to provide a method of manufacturing a three-dimensional shaped shielding material. According to a first aspect of the present invention a layered structure according to the present invention is provided. The layered structure comprises a layered structure comprising: a plastic substrate; at least one intermediate metallic layer on top of said elongated plastic substrate; a metal or metal alloy layer deposited on top of said intermediate metallic layer. The metal or metal alloy layer comprises a solidified layer applied from the melt of a metal or metal alloy. A preferred method to apply the metal or metal alloy layer is by hot dip. Hot dip application of a metal or metal alloy layer comprises the dipping of a substrate in a molten metal or metal alloy bath. Since the melting point of a plastic substrate is generally low and in many cases lower than the temperature of the molten metal bath, up to now the application of a hot dip coating on a plastic substrate was impossible. According to the present invention, before the hot dip coating is applied on the plastic substrate, an intermediate metallic layer with a rather high melting point is applied on the plastic substrate. This intermediate metallic layer protects the plastic substrate from melting and shrinking during the hot dip treatment. The metal or metal alloy layer may comprise any metal or metal alloy. Preferably, the metal or metal alloy layer has a relatively low melting point, for example a melting point lower than 450° C. More preferably, the metal or metal alloy layer has a meting point lower than 300° C., for example lower than 250° C. Preferred metal or metal alloys comprise tin or tin alloys or zinc or zinc alloys. As tin alloys one can consider for example tin-lead alloys, tin-copper or tin-silver alloys. As zinc alloys one can consider for example zinc-aluminium alloys. A tin or tin alloy layer offers the layered structure good shielding characteristics. These shielding characteristics can further be improved by adding an alloying element such as silver. Tin is a metal with a low melting point and a high ductility. It can easily be deformed. The good deformability of tin is an important characteristic since in many shielding applications it is required that the layered structure is deformed, for example three-dimensionally deformed. Due to the high ductility of tin, the layered structure according to the present invention can be deformed, for example by deep-drawing, without creating cracks. The shielding characteristics do not deteriorate due to the deformation. The thickness of the metal or metal alloy layer is preferably between 1 and 20, more preferably the thickness of the metal or metal alloy layer is between 1 and 15 μm, for example between 2 and 8 μm. The metal or metal alloy layer applied by hot dip generally has at the surface of the layer a grain size of at least 5 μm, for example 10 μm. The plastic substrate is preferably made of a thermoplastic material. Preferred plastic substrates are polyamides, polyimides, polyolefins such as polymers and copolymers of ethylene and propylene, polyetherimide, halogenated polyolefins such as polytetrafluoroethylene, polysufones, polycarbonates, polyesters, polyethylene terephtalate, polybutylene terephthalate, acrylonitrile-butadiene-styrene (ABS), polystyrene an polyvinylchloride. Possibly one or more additives such as fillers are added to the plastic substrate. The function of a filler is for example to modify the modulus and stiffness of the substrate. Examples of fillers are minerals, metals, metal oxides, metal salts and mixtures thereof. Well known fillers are for example alumina, carbon black and quartz. Other additives may comprise plasticizers, colorants and/or heat and light stabilizers. The plastic substrate has preferably a thickness between 10 and 500 μm, for example 150 μm. The plastic substrate can be an elongated plastic substrate such as a tape, a sheet or a foil. The intermediate metallic layer preferably has a sufficiently high melting point to withstand the temperature of the molten metal or metal alloy and to protect the plastic substrate from shrinking during the application of the metal or metal alloy layer. Preferably, the intermediate metallic layer has a melting point higher than 500° C., more preferably the intermediate metallic layer has a melting point higher than 600° C. The intermediate metallic layer can for example be a nickel layer, a copper layer, an aluminium layer, a cobalt layer or a chrome layer or the intermediate layer may comprise an alloy of one of these metals. The thickness of the intermediate metallic coating is preferably between 0.025 and 2 μm. More preferably, the thickness of the intermediate metallic coating is between 0.1 and 1 μm, for example 0.2 μm. The intermediate metallic layer can be applied by any technique known in the art for example by chemical plating, electroplating, spraying, evaporation, chemical vapour deposition or sputter deposition for example magnetron sputtering or ion beam sputtering. A preferred technique to apply the intermediate coating is by sputter deposition. Possibly, a number of intermediate metallic layers are deposited before a metal or metal alloy hot dip layer is applied. In a preferred embodiment a first intermediate metallic layer deposited on the plastic substrate comprises a nickel layer; a second intermediate metallic layer deposited on said first intermediate metallic layer comprises a copper layer. Possibly, an alloy layer is formed at the interface of the intermediate metallic layer and the hot dip metal or metal alloy layer. Such an alloy layer is for example present at the interface of a copper layer as intermediate metallic layer and a hot dip applied tin or tin alloy layer since copper easily forms an alloy with tin. The layered structure according to the present invention may be three-dimensionally deformed. The layered structure provided by the present invention is in particular suitable to be used as shielding material against interfering radiation. According to a second aspect of the present invention a method of manufacturing a layered structure is provided. The method comprises the following steps: providing a plastic substrate; applying at least one intermediate metallic layer on said plastic substrate; applying a metal or metal alloy layer on said intermediate metallic layer from the melt of a metal or metal alloy and solidifying this metal or metal alloy layer. The metal or metal alloy layer is preferably applied by hot dip. Preferred metal or metal alloy layers comprise tin or a tin alloy or zinc or a zinc alloy. The method according to the present invention has the advantage over other methods known in the art that the layered structure can be manufactured at low costs. The application of a coating by hot dip is more economic than the application of a coating by other techniques such as electrolysis. The intermediate metallic layer can be applied by any technique known in the art for example by chemical plating, electroplating, spraying, evaporation, chemical vapour deposition or sputtering for example magnetron sputtering, ion beam sputtering. A preferred method comprises the steps of: providing a plastic substrate; depositing a first intermediate metallic layer on said plastic substrate; said first intermediate metallic layer comprising nickel; depositing a second intermediate metallic layer on said first intermediate metallic layer; said second intermediate metallic layer comprising copper; applying a metal or metal alloy layer on said second intermediate metallic layer from the melt of a metal or metal alloy and solidifying this metal or metal alloy. The metal or metal alloy layer is preferably applied by hot dip. According to a third aspect of the present invention a method of manufacturing a shielding material is provided. The method comprises the step of deforming a layered structure as described above and/or the step of placing this layered structure in an injection mould and injection-moulding a plastic material in the mould. The deforming may comprise a three-dimensional deforming. Since a layered structure according to the present invention can be deformed without deterioration of the shielding characteristics, a shielding material obtained by the above described method is characterized by good shielding characteristics. A preferred deforming method comprises deep-drawing or thermoforming of the layered structure. The layered structure can be cold drawn or formed into to the desired shape. However, the layered structure is preferably heated for example to a temperature between 150 and 200° C. and more preferably to a temperature between 175 and 200° C. before being formed into the desired shape (thermoforming). In a moulding operation the layered structure is placed in a mould. In a subsequent step the mould cavity is filled with a polymer flowing into the recesses of the mould. A preferred method comprises the deforming of a layered structure according to the present invention, followed by a moulding operation. According to a further aspect of the present invention, a shielding material obtainable by a deforming and/or moulding operation is provided. The shielding material is for example a three-dimensionally shaped material such as a box or container. Such a box or container-like shielding material can serve as a housing to shield a device placed in the box or container-like shielding material. A shielding material according to the present invention is in particular suitable to be used as shielding material in personal computers, mobile telephones or other electronic instruments detailed-description description="Detailed Description" end="lead"? |
Medical connected container assembly and method of producing the same |
Two continuous films are sealed with each other by melting, bag type compartments are continuously formed, and a port member is provided at one side or both sides of side edges of each bag type compartment, and simultaneously, a relaxation means such as a notch at a jointing part of compartments or a connection part are provided to release tension caused by melt sealing of the adjacent port members in connected state, and thereby, a flat type connected container is provided. |
1. Multiple connected medical containers comprising: a continuous film having a melted sealed part; bag type compartments which are continuously provided by the melted sealed part; a port member which is provided at one side or both sides of side edges of each bag type compartment; and a relaxation means for releasing stress or tension at side edges of the continuous film. 2. Multiple connected medical containers according to claim 1, wherein the relaxation means is a jointing part of compartments or a connection part, each having a notch. 3. Multiple connected medical containers according to claim 2, wherein the notch is a slit, a V-shaped notch, or a U-shaped notch. 4. Multiple connected medical containers according to claim 1, wherein the relaxation means releases stress or tension by heating the side edges before or after providing the port member. 5. Multiple connected medical containers according to claim 1, wherein the relaxation means is a connection part which is provided between adjacent jointing parts of compartments without melting and sealing. 6. Multiple connected medical containers according to claim 1, further comprising a folding seam on the jointing part of compartments or the connection part so that every set number of bag type compartments is folded without the port members stacking on each other. 7. Multiple connected medical containers according to claim 6, wherein the jointing part of compartments has a width greater than a maximum diameter of the port member. 8. Multiple connected medical containers according to claim 1, wherein the port members are disposed toward the side edge of the bag type compartment so that every set number of bag type compartments is folded without the port members stacking on each other. 9. Multiple connected medical containers according to claim 1, wherein the port members are provided on alternating sides after every set number of the port members to the number of folds so that every set number of bag type compartments are folded without the port members stacking on each other. 10. Multiple connected medical containers according to claim 1, wherein the folding seam has perforations, notches, or discontinuous slits provided on the jointing part of compartments or the connection part. 11. Multiple connected medical containers according to claim 1, wherein the continuous film is in a form of tubular, a laminate of two films, or a two stacked layers film provided by folding a film having a wide width. 12. Multiple connected medical containers according to claim 1, wherein the continuous film is a plastic film being a single layer or a laminate with a thickness of 100˜500 μm. 13. Multiple connected medical containers according to claim 1, wherein the continuous film contains joining faces made by a melt sealable resin. 14. Multiple connected medical containers according to claim 1, used for continuous transfusion fluid bags or CAPD bags. 15. Multiple connected medical containers according to claim 1, comprising a hole for suspension provided at the melted sealed part of either port member. 16. A packing method of multiple connected medical containers, comprising a step of: folding the continuous multiple connected medical containers according to any one of claims 1 to 15 by a set number of two or more bag type compartments without the port members stacking on each other. 17. A packaging method of multiple connected medical containers, comprising a step of: packing the multiple connected medical containers so that compartments at a starting end and a finishing end in the multiple connected medical containers are taken out of the packaging unit, when the multiple connected medical containers according to claim 1 are packed into a packaging case (packaging unit) while being folded from a bottom of the case in order. 18. A manufacturing method of multiple connected medical containers, comprising steps of: supplying two stacked pieces of a film to a melt sealer; sealing by melting a jointing part of a compartment except for an attachment part of a port member; pulling apart one or both side edges of the film where the attachment part of a port member is provided; sealing by melting the port member; and providing a notch at the side edges of the jointing part of compartments either before or after sealing by melting the port member. 19. A manufacturing method of multiple connected medical containers, comprising steps of: supplying two stacked pieces of a film to a melt sealer; sealing by melting a jointing part of a compartment except for an attachment part of a port member; pulling apart one or both side edges of the film where the attachment part of a port member is provided; forming multiple connected containers by melting and sealing the port member; and heating the side edges or the entirety of the containers to relieve tension. 20. A contents filling method of multiple connected medical containers, comprising steps of: supplying the multiple connected medical containers according to any one of claims 1 to 15 to a contents filling device continuously; and filling contents into the multiple connected medical containers. |
<SOH> BACKGROUND ART <EOH>In the past, resin bottles formed using a blow molding method came to be employed in place of glass bottles as medical containers such as transfusion fluid bags or CAPD bags. Currently, there is a shift to an arrangement in which plastic film is sealed and formed into the shape of a bag, and a port member is attached to the bag by melting. Since these bag type medical containers have high pliability, and the volume of each container automatically reduced as the contained fluid is discharged, secondary air introduction is not required. As a result, introduction of contaminants such as microscopic dust particles or bacteria suspended in room air can be prevented. In addition, since containers of this type significantly reduce the amount and weight of waste, it is thought that they will be increasingly employed in the future. Bag type medical containers described above may be sealed so as to be bag type compartments in a continuous piece of film except sealing at the port member. This process for forming the bag is highly efficient, the required machinery is simple and requires little space, and productivity is high. In general, however, the port member is not attached until the bags have been formed and cut apart into sheets. Proposals have been made which improve an embodiment of a connected container that is produced by a process that is continuous through the attachment of the port member (Japanese Unexamined Patent Application, First Publication No. 2001-112847). However, in this case as well, it is necessary to cut free each container after attaching the port member to the container, and supply the containers one at a time to a contents filling equipment. Therefore, a large and complicated mechanical structure is required in order to position and fix each bag type container cut free in place during delivery, storage, relay, and contents filling process since the container is pliable, and for storage, packaging, and transport of the container after filling. It is thus difficult to respond if changes are made in the dimensions of the container and adjustments in the devices are difficult. In addition, because maintaining the machinery is troublesome and breakdowns occur, manufacturing costs tend to rise. Furthermore, the bag-forming process and the filling process are independent processes. In addition, since the container is pliable, it does not have a fixed shape. Thus, relay, packing, and feeding to the contents filling equipment is difficult. In addition, since the container itself is not self-supporting, it is difficult to hold its shape. As a result, when the containers are stacked, problems can readily occur such as a load shift, deformation, scratch, and the like, so that troublesome special handling is needed. Thus, it is often the case that the volume-to-container capacity remarkably increases, and efficiency during the production process is poor. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 shows multiple connected medical containers according to the present invention (without connection parts) in which port members are provided at both sides of side edges. FIG. 2 is a conceptual view in which the multiple connected medical containers shown in FIG. 1 are folded. FIG. 3 shows the way to continuously take out packaged multiple connected medical containers. FIG. 4 shows multiple connected medical containers according to the present invention (with connection parts) in which port members are provided at both sides of side edges. FIG. 5 shows multiple connected medical containers according to the present invention in which a port member is provided at one side of side edges detailed-description description="Detailed Description" end="lead"? |
Stamp having an antisticking layer and a method of forming of repairing such a stamp |
A stamp for use in transferring a pattern in nano-scale has a monomolecular antisticking layer. The anti-sticking layer comprises molecular chains, which are covalently bound to the surface of the stamp and which each comprise at least one fluorine-containing group. Each molecular chain contains a group Q, which comprises a bond which is weaker than the other bonds in the molecular chain as well as the covalent bond that binds the molecular chain to the surface of the stamp. Splitting of said bond in the group Q creates a group Q1, which is attached to the part of the molecular chain being left on the surface of the stamp and which is capable of reacting with a fluorine-containing compound to restore the antisticking layer. In a method of manufacturing a stamp for use in transferring a pattern in nanoscale, the stamp is provided with the above-mentioned molecular chain. In a method of repairing a damaged antisticking layer of the above-mentioned stamp, the stamp is treated with a repairing reagent, which has a coupling end, which is capable of reacting with the group Q1, and a fluorine-containing group located at the other end of the repairing reagent. |
1. A stamp for use in transferring a pattern in nanoscale, which stamp has a monomolecular antisticking layer, characterised in that said antisticking layer comprises molecular chains, which are covalently bound to the surface of the stamp and which each comprise at least one fluorine-containing group, each molecular chain containing a group Q, which comprises a bond which is weaker than the other bonds in the molecular chain as well as the covalent bond that binds the molecular chain to the surface of the stamp, splitting of said bond in the group Q creating a group Q1, which is attached to the part of the molecular chain being left on the surface of the stamp and which is capable of reacting with a fluorine-containing compound to restore the antisticking layer. 2. A stamp as claimed in claim 1, in which the antisticking layer comprises a silane group. 3. A stamp as claimed in claim 2, in which the surface of the stamp is made of a material M, which is selected from silicon, aluminium, nickel, chromium and titanium or oxides thereof, the silane group of the antisticking layer being bound to the surface by means of at least one group B1, which is selected from M- and M-O—. 4. A stamp as claimed in claim 3, in which the antisticking layer has a first part, which has the general formula (B1)3-nR′nSiR1X1, where n is 0, 1 or 2, R′ is an aliphatic, saturated carbon compound, Si is the silane group, R1 is a carbon chain and where X1 is a first coupling group, and a second part, which has the general formula X2R2, where X2 is a second coupling group which is bound to X1 and which together with X1 forms the group Q and where R2 is a fluorine-containing hydrocarbon compound. 5. A stamp as claimed in claim 4, in which R1 is a carbon chain which has a length from the silane group to X1 of 2-10 carbon atoms and preferably is saturated and unsubstituted. 6. A stamp as claimed in claim 4, in which R2 is a carbon chain which has a length from the end group to X2 of 2-10 carbon atoms and preferably comprises at least one perfluorinated carbon atom and is saturated. 7. A stamp as claimed in claim 6, in which R2 is branched at the free end, each branch comprising at least one perfluorinated carbon atom. 8. A stamp as claimed in claim 4, in which n is 0. 9. A stamp as claimed in any one of the preceding claims, in which the group Q is a sulphur bridge. 10. A method of manufacturing a stamp for use in transferring a pattern in nanoscale, which stamp has a monomolecular antisticking layer, characterised in that the surface of the stamp is provided with molecular chains, which are covalently bound to the surface of the stamp and which each comprise at least one fluorine-containing group and a group Q, which comprises a bond which is weaker than the other bonds in the molecular chain as well as the covalent bond that binds the molecular chain to the surface of the stamp, splitting of said bond in the group Q creating a group Q1, which is attached to the part of the molecular chain being left on the surface of the stamp and which is capable of reacting with a fluorine-containing compound to restore the antisticking layer. 11. A method as claimed in claim 10, in which the surface of the stamp is treated by being reacted with a first reagent, which has a first functional group, which is hydrolysable, and a second functional group, thus binding the first functional group of the first reagent to the surface of the stamp, subsequently treating the surface of the stamp with a second reagent, which has a first end, which is capable of reacting with the second functional group of the first reagent, and a second end, which comprises at least one fluorine-containing group, and binding the first end of the second reagent to the second functional group of the first reagent, thereby forming the group Q. 12. A method as claimed in claim 11, in which the first reagent is converted into gaseous phase before it is reacted with the surface of the stamp. 13. A method as claimed in claim 11 or 12, in which the treatment with the second reagent is carried out in liquid phase. 14. A method of repairing a damaged monomolecular antisticking layer on a stamp as claimed in claim 1, characterised in that the stamp is treated with a repairing reagent, which has a coupling end, which is capable of reacting with the group Q1, and a fluorine-containing group located at the other end of the repairing reagent, that the coupling end of the repairing reagent is bound to the group Q1 which is attached to the surface of the stamp, the group Q being formed anew. 15. A method as claimed in claim 14, in which the stamp is first treated for splitting substantially all groups Q. |
<SOH> BACKGROUND ART <EOH>In the replication of nanostructures, use is often made of a stamp, which hot embosses a pattern into a plate coated with a suitable polymer, such as a thermoplastic. It is necessary to provide an antisticking boundary surface between the patterned stamp and the polymer to prevent thermoplastic from getting stuck to and contaminating the surface of the stamp when the stamp is released from the coated plate after embossing. Also the pattern replicated on the plate can be damaged by such sticking. For successful embossing, the stamp must thus be chemically and mechanically stable and have a low tendency to stick to polymers. In Microelectronic Engineering 35 (1997) 381-384, R. W. Jaszewski et al. disclose that the surface of the stamp can be covered with an ultra-thin, antisticking layer of PTFE. The layer is precipitated by means of plasma polymerisation or ion sputtering from a plasma. According to Jaszewski et al., the quality of the film deteriorates in the embossing. Obviously, the film is not sufficiently stable. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the present invention, the above drawbacks are obviated or reduced and a stamp with an antisticking layer is obtained, which is stable, has good antisticking properties and can easily be repaired when damaged or worn. More specifically, the invention provides a stamp for use in transferring a pattern in nanoscale, which stamp has a monomolecular antisticking layer and is characterised in that said antisticking layer comprises molecular chains, which are covalently bound to the surface of the stamp and which each comprise at least one fluorine-containing group, each molecular chain containing a group Q, which comprises a bond which is weaker than the other bonds in the molecular chain as well as the covalent bond that binds the molecular chain to the surface of the stamp, splitting of said bond in the group Q creating a group Q1, which is attached to the part of the molecular chain being left on the surface of the stamp and which is capable of reacting with a fluorine-containing compound to restore the antisticking layer. The invention further relates to a method of manufacturing a stamp for use in transferring a pattern in nanoscale, which stamp has a monomolecular antisticking layer, said method being characterised in that the surface of the stamp is provided with molecular chains, which are covalently bound to the surface of the stamp and which each comprise at least one fluorine-containing group and a group Q, which comprises a bond which is weaker than the other bonds in the molecular chain as well as the covalent bond that binds the molecular chain to the surface of the stamp, splitting of said bond in the group Q creating a group Q1, which is attached to the part of the molecular chain being left on the surface of the stamp and which is capable of reacting with a fluorine-containing compound to restore the antisticking layer. The invention also relates to a method of repairing a damaged monomolecular antisticking layer on a stamp as stated above, which method is characterised in that the stamp is treated with a repairing reagent, which has a coupling end, which is capable of reacting with the group Q1, and a fluorine-containing group located at the other end of the repairing reagent, that the coupling end of the repairing reagent is bound to the group Q1 which is attached to the surface of the stamp, the group Q being formed anew. Further advantages and features of the invention will be apparent from the description below and the appended claims. detailed-description description="Detailed Description" end="lead"? |
Interface circuit for connecting to an output of a frequency converter |
In an interface circuit for connection to an output of a frequency converter, at least two current paths are coupled to one another in parallel. Each current path includes at least one cascode stage for signal processing. The circuit compensates for DC voltage offsets of the frequency converter, and has a gain ratio that can be changed over for signals with a large dynamic range. |
1-7. (canceled) 8. An interface circuit for connection to an output of a frequency converter, comprising: a signal input; a signal output; a first current path, which couples the signal input to the signal output and comprises at least one cascode stage; a second current path, which comprises a cascode stage connected in parallel with the cascode stage of the first current path; one of the first and second current paths having a connection for receiving a common-mode signal; and a third current path, which comprises a cascode stage coupled in parallel with the cascode stages of the first and second current paths, the cascode stages in the second and third current paths each having a control input connected to a bias stage that is operable for changing over between the second and third current paths. 9. The interface circuit as claimed in claim 8, wherein the bias stage has an output coupled to the cascode stages in the first and second current paths for supplying bias voltage. 10. The interface circuit as claimed in claim 9, wherein the bias stage has a control input and is responsive to a control signal at the control input thereof for putting the interface circuit into a current-saving mode. 11. The interface circuit as claimed in claim 10, including a current divider which couples the signal output, the connection for providing a common-mode signal, and the cascode stage in the first current path. 12. The interface circuit as claimed in claim 9, including a current divider which couples the signal output, the connection for providing a common-mode signal, and the cascode stage in the first current path. 13. The interface circuit as claimed in claim 8, including a current divider which couples the signal output, the connection for providing a common-mode signal, and the cascode stage in the first current path. 14. The interface circuit as claimed in claim 13, including a control loop for common-mode rejection, having a control input connected to the connection for providing a common-mode signal, and having an output coupled to the signal input. 15. The interface circuit as claimed in claim 14, wherein the bias stage has an output coupled to the cascode stages in the first and second current paths for supplying bias voltage. 16. The interface circuit as claimed in claim 15, wherein the bias stage has a control input and is responsive to a control signal at the control input thereof for putting the interface circuit into a current-saving mode. 17. The interface circuit as claimed in claim 8, including a control loop for common-mode rejection, having a control input connected to the connection for providing a common-mode signal, and having an output coupled to the signal input. 18. The interface circuit as claimed in claim 17, wherein the bias stage has an output coupled to the cascode stages in the first and second current paths for supplying bias voltage. 19. The interface circuit as claimed in claim 18, wherein the bias stage has a control input and is responsive to a control signal at the control input thereof for putting the interface circuit into a current-saving mode. 20. The interface circuit as claimed in claim 19, wherein the control loop for common-mode rejection comprises means for stabilizing the control loop. 21. The interface circuit as claimed in claim 20, including a current divider which couples the signal output, the connection for providing a common-mode signal, and the cascode stage in the first current path. 22. The interface circuit as claimed in claim 18, wherein the control loop for common-mode rejection comprises means for stabilizing the control loop. 23. The interface circuit as claimed in claim 22, including a current divider which couples the signal output, the connection for providing a common-mode signal, and the cascode stage in the first current path. 24. The interface circuit as claimed in claim 17, wherein the control loop for common-mode rejection comprises means for stabilizing the control loop. 25. The interface circuit as claimed in claim 24, including a current divider which couples the signal output, the connection for providing a common-mode signal, and the cascode stage in the first current path. 26. The interface circuit as claimed in claim 8, wherein the signal input, the signal output and the current paths are for processing symmetrical signals. |
SOLUBLE STEROIDAL PEPTIDES FOR NUCLEIC ACID DELIVERY |
Amphiphilic lipopeptide compositions for gene delivery are disclosed. An illustrative amphiphilic lipopeptide composition includes a human protamine 2 peptide conjugated to a hydrophobic moiety. Illustrative hydrophobic moieties include sterols, bile acids, and fatty acids. The amphiphilic lipopeptide composition is mixed with a nucleic acid such that the nucleic acid binds to the peptide portion of the lipopeptide. This mixture is placed in contact with mammalian cells to effect transfection of the cells with the nucleic acid. A method of making such amphiphilic lipopeptides is also described. |
1. A composition comprising a PRM2 peptide conjugated to a hydrophobic moiety. 2. The composition of claim 1 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2. 3. The composition of claim 1 wherein said hydrophobic moiety comprises a sterol. 4. The composition of claim 3 wherein said sterol is a member selected from the group consisting of cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, and ergocalciferol. 5. The composition of claim 3 wherein said sterol comprises cholesterol. 6. The composition of claim 1 wherein said hydrophobic moiety comprises a bile acid. 7. The composition of claim 6 wherein said bile acid is a member selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid. 8. The composition of claim 3 wherein said bile acid comprises lithocholic acid. 9. The composition of claim 1 wherein said hydrophobic moiety comprises a fatty acid. 10. The composition of claim 9 wherein said fatty acid is a member selected from the group consisting of C4-C20 alkanoic acids. 11. The composition of claim 9 wherein said fatty acid is a member selected from the group consisting of butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid. 12. The composition of claim 1 wherein said PRM2 peptide is conjugated to said hydrophobic moiety through a peptide linkage. 13. The composition of claim 12 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2, and said hydrophobic moiety comprises cholesterol. 14. The composition of claim 12 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2, and said hydrophobic moiety comprises lithocholic acid. 15. The composition of claim 1 wherein said hydrophobic moiety is conjugated to said PRM2 peptide through a non-terminal amino acid residue. 16. A composition comprising a mixture of a nucleic acid and a conjugate comprising a PRM2 peptide and a hydrophobic moiety. 17. The composition of claim 16 wherein said nucleic acid binds to said PRM2 peptide. 18. The composition of claim 16 wherein said nucleic acid comprises a plasmid. 19. The composition of claim 16 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2. 20. The composition of claim 16 wherein said hydrophobic moiety comprises a sterol. 21. The composition of claim 20 wherein said sterol is a member selected from the group consisting of cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, and ergocalciferol. 22. The composition of claim 20 wherein said sterol comprises cholesterol. 23. The composition of claim 16 wherein said hydrophobic moiety comprises a bile acid. 24. The composition of claim 23 wherein said bile acid is a member selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid. 25. The composition of claim 20 wherein said bile acid comprises lithocholic acid. 26. The composition of claim 16 wherein said hydrophobic moiety comprises a fatty acid. 27. The composition of claim 26 wherein said fatty acid is a member selected from the group consisting of C4-C20 alkanoic acids. 28. The composition of claim 26 wherein said fatty acid is a member selected from the group consisting of butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid. 29. The composition of claim 16 wherein said PRM2 peptide is conjugated to said hydrophobic moiety through a peptide linkage. 30. The composition of claim 29 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2, and said hydrophobic moiety comprises cholesterol. 31. The composition of claim 29 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2, and said hydrophobic moiety comprises lithocholic acid. 32. The composition of claim 16 wherein said hydrophobic moiety is conjugated to said PRM2 peptide through a non-terminal amino acid residue. 33. The composition of claim 16 wherein said nucleic acid encodes interleukin-12. 34. The composition of claim 33 wherein said nucleic acid comprises p2CMVmIL-12. 35. A method for transfecting a mammalian cell comprising contacting said cell with a composition comprising a mixture of a nucleic acid and a conjugate comprising a PRM2 peptide and a hydrophobic moiety, and then incubating said cell under conditions suitable for growth thereof. 36. The method of claim 35 wherein said mammalian cell is a human cell. 37. The method of claim 35 wherein said nucleic acid binds to said PRM2 peptide. 38. The method of claim 35 wherein said nucleic acid comprises a plasmid. 39. The method of claim 35 of claim 1 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2. 40. The method of claim 35 wherein said hydrophobic moiety comprises a sterol. 41. The method of claim 40 wherein said sterol is a member selected from the group consisting of cholestanol coprostanol cholesterol, epicholesterol, ergosterol, and ergocalciferol. 42. The method of claim 40 wherein said sterol comprises cholesterol. 43. The method of claim 35 wherein said hydrophobic moiety comprises a bile acid. 44. The method of claim 43 wherein said bile acid is a member selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid. 45. The method of claim 43 wherein said bile acid comprises lithocholic acid. 46. The method of claim 35 wherein said hydrophobic moiety comprises a fatty acid. 47. The method of claim 46 wherein said fatty acid is a member selected from the group consisting of C4-C20 alkanoic acids. 48. The method of claim 46 wherein said fatty acid is a member selected from the group consisting of butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid. 49. The method of claim 35 wherein said PRM2 peptide is conjugated to said hydrophobic moiety through a peptide linkage. 50. The method of claim 49 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2, and said hydrophobic moiety comprises cholesterol. 51. The method of claim 49 wherein said PRM2 peptide comprises a peptide identified as SEQ ID NO:2, and said hydrophobic moiety comprises lithocholic acid. 52. The method of claim 35 wherein said hydrophobic moiety is conjugated to said PRM2 peptide through a non-terminal amino acid residue. 53. An plasmid configured for expressing p35 and p40 subunits of interleukin-12 under control of at least one cytomegalovirus promoter. 54. The plasmid of claim 53 wherein said plasmid is p2CMVmIL-12. 55. A method for making an amphiphilic lipopeptide comprises conjugating a hydrophobic moiety to a non-terminal amino acid residue of a PRM2 peptide. |
<SOH> BACKGROUND OF THE INVENTION <EOH>This invention relates to gene delivery. More particularly, this invention relates to compositions of matter and methods of use and making thereof for gene delivery wherein the compositions of matter comprise amphiphilic lipoproteins configured for binding nucleic acids. Progress in the area of gene delivery has been tremendous in the last several years, yet in clinical settings the dream of a successful therapy based on nucleic acids remains a frustrating riddle. Gene delivery vectors have been largely put into either of two categories, viral or non-viral, and most of the published reports have focused on circumventing the deficiencies inherent in both types of vectors. Factors such as toxicity, permanently altering the host genome through recombination events with viral vectors, and poorly optimized delivery capabilities with non-viral vectors demand application of concepts that have clinical relevance in terms of safety, efficacy, and patient compliance. However, by now its clear that feasibility of a single vector serving as a universal gene carrier for all disease targets is remote and impractical. In cancer immunotherapy, for example, the use of cytokines such as interleukin-12, which is a proven anti-proliferative cytokine in confinement and inhibition of tumor progression and metastasis in several types of cancers in vivo, is of great interest. Although cytokine gene therapy has been attempted with a variety of viral vectors, such as adenovirus, retroviris, adeno-associated viruses, and lentiviruses, there is still a growing need to optimize non-viral gene carriers with unprecedented safety and efficacy profiles. Among existing non-viral gene carriers polyethyleneimine, and lipid-protamine-DNA (LPD) lipoplexes have had some success in terms of cytokine gene transfer efficiency, however the issues related to carrier-associated toxicities are poorly understood. Cationic lipids are water insoluble and require the formation of liposomes using a colipid, such as dioleyl phophatidylethanolamine (DOPE) or cholesterol in presence of organic solvents, which involves multiple steps. Although their gene transfer applications have been under investigation since 1987, the exact mechanism elucidating their structure-function relationship has not been completely revealed. It is believed that lipid anchors, such as steroids and fatty acid chains, serve to provide amphiphilic character to these carriers, which would orient the head group surface charge more favorably, and also take part in hydrophobic interactions with plasma and organelle membranes. Lipid anchors can also interact specifically with various membrane receptors for enhanced cellular uptake and lipid-mediated transduction. Polyethyleneimine and Starburst™ dendrimers, due to their high transfection efficiency, have received a lot of attention and remain, by far, the most effective cationic polymers for transfection created to date. The functioning of these polymers has been attributed to the so-called proton sponge effect due to secondary and tertiary amines present in these polymers, which supposedly leads to disruption inside endosomes and endo-lysosomes by osmotic swelling. Gene carriers that would combine the concepts of water solubility, amphiphilic nature, lipid mediated membrane interactions, endosomal buffering, and nuclear targeting would be an exciting option for plasmid based gene therapy. Peptide based gene delivery systems are least investigated, and their applications in delivering cytokine genes are virtually unexplored. Several different types of peptides that possess endosomolytic, fusogenic, or membrane permeabilizing properties derived from various viruses, such as vesicular stomatitis virus glycoprotein (VSVG) and influenza virus hemaglutinin, have been used either alone or in combination with liposomes and polymers. Co-polymers of lysine and histidine have also been shown to efficiently deliver genes inside cells, and this property has been attributed to the imidazole ring of the histidine side chain, which behaves as an endosomal rupturing agent. While prior compositions and methods for delivering peptides are known and are generally suitable for their limited purposes, they possess certain inherent deficiencies that detract from their overall utility. For example, polyethyleneimine is effective only in high molecular weight (>10,000 M.W.) formulations, but such high molecular weight compositions can be toxic, elicit immune responses, are non-biodegradable, are not site specific, and condense plasmid DNA too tightly. Cationic lipids can be toxic at therapeutic doses, elicit immune responses, require several steps to synthesize and involve the use of organic solvents, are water insoluble, offer little inherent endosomal buffering, and are not site specific. Current peptide-based gene carriers may be toxic at therapeutic doses, elicit immune responses, often require cationic lipids for effectiveness, frequently are subject to aggregation, and exhibit poor water solubility due to hydrophobic amino acid residues. In view of the foregoing, it will be appreciated that providing compositions and methods for delivering peptides, especially cytokines, would be a significant advancement in the art. |
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>These and other objects can be addressed by providing a composition comprising a PRM2 peptide conjugated to a hydrophobic moiety. In one illustrative embodiment of the invention, the PRM2 peptide comprises a peptide identified herein as SEQ ID NO:2. The hydrophobic moiety illustratively comprises a sterol, a bile acid, or a fatty acid. Illustrative sterols include cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, and ergocalciferol. Examples of bile acids include cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid. Examples of fatty acids include C 4 -C 20 alkanoic acids, such as butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid. In another illustrative embodiment of the invention, the PRM2 peptide is conjugated to the hydrophobic moiety through an amide (peptide) linkage. Other linkers known in the art may also be used according to the invention. The hydrophobic moiety can be conjugated to the PRM2 peptide through a non-terminal amino acid residue, thus forming a “T-shaped” conjugate. Another illustrative embodiment of the invention comprises a mixture of a nucleic acid and a conjugate comprising a PRM2 peptide and a hydrophobic moiety. The nucleic acid binds to the PRM2 peptide portion of the conjugate. The nucleic acid can be a plasmid or other type of nucleic acid known in the art for gene delivery. Still another illustrative embodiment of the invention comprises a method for transfecting a mammalian cell, such as a human cell, comprising contacting the cell with a composition comprising a mixture of a nucleic acid and a conjugate comprising a PRM2 peptide and a hydrophobic moiety, and then incubating the cell under conditions suitable for growth thereof. Yet another illustrative embodiment of the invention comprises a plasmid configured for expressing p35 and p40 subunits of interleukin-12 under control of at least one cytomegalovirus promoter. An illustrative configuration of this plasmid is p2CMVmIL-12. |
Arrangement and method for supplying implant fixtures made principally of titanium |
In an arrangement and method for supplying implant fixtures (2) made of titanium with surface structures and added bone-growth-stimulating agents or substances, the fixtures are prepared for selective use in different implantation situations. One or more first devices (9) are intended, by means of surface treatments, for example in the form of etching, shot-peening, plasma spraying and/or electrochemical treatment (so-called anodic oxidation), to supply fixtures (13-20) with different surface structures. One or more second devices (21) are intended to apply calcium phosphate layers in different dose qpplications onto implant fixtures divided into different ranges (partial ranges) (11, 12), which dose applications create layer thicknesses of the order of 1 nanometer to 3000 nanometers. In addition, as an alternative or as a complement to this, one or more third devices (22) can be provided to treat implant fixtures belonging to said range, or another range (partial range) which lacks CaP layers, by applying bone-growth-stimulating substance, for example rhBMP-2 or rhBMP-7, in different dose applications with different quantity and strength. A very high degree of selectivity is achieved in this way. |
1. An arrangement for supplying implant fixtures (2) which are made principally of titanium and which, as a function of allocated surface structures and added bone-growth-stimulating or bone-growth-maintaining agents or substances, are prepared for selective use in different implantation situations (cases), characterized in that one or more first devices (9) are intended, by means of surface treatments, for example in the form of etching, shot-peening, plasma spraying and/or electrochemical treatment (so-called anodic oxidation), to supply fixtures (13-20) with different surface structures and/or oxide layers provided with porosities, and involving one or both of the following alternatives: a) one or more second devices (21) are intended to apply calcium phosphate layers (CaP layers) in different dose applications onto implant fixtures divided into or forming different ranges (partial ranges) (11, 12), which dose applications create calcium phosphate layers of the order of 1-3000 nanometers, preferably 100-2000 nanometers, and b) one or more third devices (22) are provided to treat implant fixtures belonging to one or more of said ranges (partial ranges), or to another range (partial range) which lacks calcium phosphate layers, by applying bone-growth-stimulating substance, for example rhEMP, in different dose applications, for example in dose applications involving about 0.05-50 p.g, preferably 5-20 μg, of bone-growth-stimulating substance, for example rhBMP-2 or rhBMP-7. 2. The arrangement as claimed in patent claim 1, characterized in that the first devices (9) are intended to surface-treat the surfaces by means of mechanical devices which perform mechanical working of the surfaces. 3. The arrangement as claimed in patent claim 1, characterized in that the third devices are intended to coat the relevant fixture surface(s) with ca. 5 μg calcium phosphate layers rhBMP-2 or rhBMP-7. 4. The arrangement as claimed in claim 1, characterized in that it comprises surface structures charged with a dose of less than 50 μg. 5. The arrangement according to claim 1, characterized in that it comprises surface structures with porous oxide layers with more or less open pores charged with CaP layers within the range of 1-3000 nanometers and treated with a dose or doses of bone-growth-stimulating substance. 6. Method for allocating implant fixtures (28) which are made of tissue-compatible material, preferably titanium, and with one or more surface structures and added bone-growth stimulating agents or substances, characterized in that fixtures with different surface structures and/or oxide layers provided with porosities are supplied by means of one or more first devices (9) and a) implant fixtures are allocated to a range (partial range) (11, 12) and, by means of one or more second devices (21), calcium phosphate layers (CaP layers) are applied in different dose applications which create calcium phosphate layers within a range of 1-3000 nanometers, and/or b) on implant fixtures belonging to said range with applied calcium phosphate layers, or to another range (partial range) which lacks calcium phosphate layers, one or more third devices (22) apply the bone-growth-stimulating agents or substances, for example rhEMP-2 or rhBMP-7, in different dose applications, for example in dose applications obtained by means of ca. 0.05-50 μg of bone-growth-stimulating agents or substance(s). 7. An arrangement for supplying implant fixtures made of titanium and with surfaces provided with surface structures and coated with bone-growth-stimulating and/or bone-growth-maintaining agents or substance(s), characterized by equipment for producing surface structures and a dose or doses of agents or substances on or in the respective implant/fixture, ordering equipment for transmitting orders for implant fixtures with defined surface structures and doses, equipment for receiving the ordered implant fixtures, production equipment for producing implant fixtures with defined surface structure, and application equipment for applying layers or doses of calcium phosphate and/or bone-growth-stimulating agents or substance(s), for example rhBMP-2 or rhEMP-7, on the surface structure or surface structures of the respective implant/fixture. 8. The arrangement according to patent claim 7, characterized in that the ordering equipment is intended to work with order information which includes the surface structure configuration, dose type and dose strength. 9. The arrangement as claimed in patent claim 7 or 8, characterized in that a payment function for purchasing the implant fixtures can be established via the telecommunications and/or computer network, e.g. the public telecommunications and or computer networks, which include the Internet. 10. The arrangement as claimed in patent claim 2, characterized in that the third devices are intended to coat the relevant fixture surface(s) with ca. 5 μg calcium phosphate layers rhBMP-2 or rhBMP-7. 11. The arrangement as claimed in claim 2, characterized in that it comprises surface structures charged with a dose of less than 50 μg. 12. The arrangement as claimed in claim 3, characterized in that it comprises surface structures charged with a dose of less than 50 μg. 13. The arrangement according to claim 2 characterized in that it comprises surface structures with porous oxide layers with more or less open pores charged with CaP layers within the range of 1-3000 nanometers and treated with a dose or doses of bone-growth-stimulating substance. 14. The arrangement according to claim 3, characterized in that it comprises surface structures with porous oxide layers with more or less open pores charged with CaP layers within the range of 1-3000 nanometers and treated with a dose or doses of bone-growth-stimulating substance. 15. The arrangement according to claim 4, characterized in that it comprises surface structures with porous oxide layers with more or less open pores charged with CaP layers within the range of 1-3000 nanometers and treated with a dose or doses of bone-growth-stimulating substance. 16. The arrangement as claimed in patent claim 8, characterized in that a payment function for purchasing the implant fixtures can be established via the telecommunications and/or computer network, e.g. the public telecommunications and or computer networks, which include the Internet. |
Method for controlling an automatic gearbox according to a road profile |
A method for automatically controlling the gearbox of a road vehicle uses a computer using information on displacement speed and transversal acceleration of the vehicle and engine load in order to apply various shifting rules according to the road profile. The gearbox computer applies different gear shifting rules according to the value of a coefficient of activity Kbend depending on the displacement speed of the vehicle (V), the lateral acceleration of the vehicle (Gt) and the derivative thereof in relation to time (dGt/dt). |
1. A method of controlling a road vehicle automatic transmission by computer utilizing the information regarding speed of travel and transverse acceleration of the vehicle and engine load, so as to apply various road profile dependent shift laws to the transmission, characterized in that the computer of the transmission applies various shift laws for the ratios according to the value of an activity coefficient Kcorner dependent on the speed of travel of the vehicle (V), on the lateral acceleration of the vehicle (Gt) and on its derivative with respect to time (dGt/dt). 2. The method of control as claimed in claim 1, characterized in that the computer applies various discrete change of ratio laws. 3. The method of control as claimed in claim 1, characterized in that the computer applies various continuous change of ratio variograms. 4. The method of control as claimed in claim 1, characterized in that the activity coefficient Kcorner is obtained from the product of the transverse acceleration (Gt) and its derivative with respect to time (dGt/dt). 5. The method of control as claimed in claim 4, characterized in that the product of the transverse acceleration (Gt) and its derivative with respect to time (dGt/dt) is weighted by the speed of travel of the vehicle. 6. The method of control as claimed in claim 1, characterized in that the computer adopts a set of shift laws which is suitable for roads which are not very bendy when the activity coefficient Kcorner is below a specified threshold. 7. The method of control as claimed in claim 1, characterized in that the information regarding engine load is given by the opening of the engine throttle valve. 8. The method of control as claimed in claim 1, characterized in that the information regarding engine load is given by the position of the accelerator pedal. 9. The method of control as claimed in claim 1, characterized in that the information regarding engine load is given by a measurement of the power provided by the engine. 10. The method of control as claimed in claim 1, characterized in that the information regarding engine load is given by a measurement of the torque delivered by the engine. 11. The method of control as claimed in claim 2, characterized in that the activity coefficient Kcorner is obtained from the product of the transverse acceleration (Gt) and its derivative with respect to time (dGt/dt). 12. The method of control as claimed in claim 3, characterized in that the activity coefficient Kcorner is obtained from the product of the transverse acceleration (Gt) and its derivative with respect to time (dGt/dt). 13. The method of control as claimed in claim 2, characterized in that the computer adopts a set of shift laws which is suitable for roads which are not very bendy when the activity coefficient Kcorner is below a specified threshold. 14. The method of control as claimed in claim 3, characterized in that the computer adopts a set of shift laws which is suitable for roads which are not very bendy when the activity coefficient Kcorner is below a specified threshold. 15. The method of control as claimed in claim 4, characterized in that the computer adopts a set of shift laws which is suitable for roads which are not very bendy when the activity coefficient Kcorner is below a specified threshold. 16. The method of control as claimed in claim 5, characterized in that the computer adopts a set of shift laws which is suitable for roads which are not very bendy when the activity coefficient Kcorner is below a specified threshold. 17. The method of control as claimed in claim 2, characterized in that the information regarding engine load is given by the opening of the engine throttle valve. 18. The method of control as claimed in claim 3, characterized in that the information regarding engine load is given by the opening of the engine throttle valve. 19. The method of control as claimed in claim 4, characterized in that the information regarding engine load is given by the opening of the engine throttle valve. 20. The method of control as claimed in claim 5, characterized in that the information regarding engine load is given by the opening of the engine throttle valve. |
Implant for example dental implant |
An implant (10) has one or more surfaces (10a, 10b) with a basic or starting surface structure (1a) derived from mechanical working. A topographic modification of the surface structures is arranged on said surface structure or surface structures. The topographic modification can be formed, for example, by means of shot-peening, etching, plasma spraying, chemical action, etc. The topographically modified surface structures support bone-growth-stimulating agent. In a method for producing the implant, three subsidiary methods are used for carrying out the mechanical working, the topographical modification, and the application of the bone-growth-stimulating agent. An important niche in the demand which exists in the field of implants is thus covered in an advantageous manner. |
1. An implant (fixture), for example a dental implant (10), characterized by the following combination: a) on one or more surfaces (10a, 10b), preferably outwardly directed surfaces (10a), it has an underlying basic or starting structure (1a) derived from mechanical working (milling, turning, etc.), b) on said basic or starting surface structure or surface structures (1a), it has a topographic modification (2, 3, 4) of the basic or starting surface structure (1a), which topographic modification gives, for example, a surface structure or surface structures formed by shot-peening, etching, plasma spraying and/or chemical action, and c) the topographically modified surface structure or surface structures (4) support(s) bone-growth-stimulating and/or bone-growth-maintaining agent, for example of the rhBMP type. 2. The implant as claimed in patent claim 1, characterized in that the topographically modified surface or surfaces is (are) adapted to the surrounding bone structure in question in order to afford excellent stability and a load-distributing effect in the transition zone between the implant and the bone structure. 3. The implant as claimed in patent claim 1, characterized in that the quantity of bone-growth-stimulating and/or bone-growth-maintaining agent causes a modification of the tissue (bone tissue) surrounding the implant adapted to the topographically modified surface structure or surface structures. 4. The implant as claimed in patent claim 1, characterized in that the topographically modified surface or surfaces (4) is (are) intended to bring about a good retention function for the bone-growth-stimulating and/or bone-growth-maintaining agent (5). 5. The implant as claimed in claim 1, characterized in that the topographically modified surface structure or surface structures is (are) made up of a porous layer (4). 6. The implant as claimed in claim 1, characterized in that the bone-growth-stimulating and/or bone-growth-maintaining agent or agents on the topographically modified surface structure or surface structures form(s) one or more layers of dried-in agent or substance. 7. A method for producing one or more surface structures (10a, 10b) on an implant (10) (fixture), preferably a dental implant, characterized by the following combination: a) in a first subsidiary method (6), the implant is produced from a blank (9), preferably of titanium, which is manually worked (milling, turning, etc.) to produce one or more basic or starting surface structures (1a), b) in a second subsidiary method (7), the implant with the basic or starting structure(s) thus given to it is worked with means or processes which topographically modify the basic or starting surface structure or surface structures in order to obtain one or more topographically modified or surface-specific surfaces (2, 3, 4), which modifying means or process consist of, for example, shot-peening, etching, plasma spraying, chemical working, for example anodic oxidation, laser working, etc., and c) in a third subsidiary method, the topographically modified or surface-specific surface or surfaces is (are) coated with bone-growth-stimulating and/or bone-growth-maintaining agent, for example of the rhBMP type. 8. The method as claimed in patent claim 7, characterized in that the topographically modified or surface-specific surface or surfaces (4) is (are) coated with bone-growth-stimulating and/or bone-growth-maintaining agent or substance which is dried onto the surfaces and forms one or more dried-in layers. 9. The method as claimed in claim 7 or 8, characterized in that the quantity of bone-growth-stimulating and/or bone-growth maintaining agent (5) is chosen as a function of the existing bone quality. 10. The method as claimed in patent claim 7, characterized in that the topographically modified surface structure or surface structures are chosen for optimum stability and load-distributing effect in the bone structure in question. 11. The implant as claimed in patent claim 2, characterized in that the quantity of bone-growth-stimulating and/or bone-growth-maintaining agent causes a modification of the tissue (bone tissue) surrounding the implant adapted to the topographically modified surface structure or surface structures. 12. The implant as claimed in patent claim 2, characterized in that the topographically modified surface or surfaces (4) is (are) intended to bring about a good retention function for the bone-growth-stimulating and/or bone-growth-maintaining agent (5). 13. The implant as claimed in patent claim 3, characterized in that the topographically modified surface or surfaces (4) is (are) intended to bring about a good retention function for the bone-growth-stimulating and/or bone-growth-maintaining agent (5). 14. The implant as claimed in claim 2, characterized in that the topographically modified surface structure or surface structures is (are) made up of a porous layer (4). 15. The implant as claimed in claim 3, characterized in that the topographically modified surface structure or surface structures is (are) made up of a porous layer (4). 16. The implant as claimed in claim 4, characterized in that the topographically modified surface structure or surface structures is (are) made up of a porous layer (4). 17. The implant as claimed in claim 2, characterized in that the bone-growth-stimulating and/or bone-growth-maintaining agent or agents on the topographically modified surface structure or surface structures form(s) one or more layers of dried-in agent or substance. 18. The implant as claimed in claim 3, characterized in that the bone-growth-stimulating and/or bone-growth-maintaining agent or agents on the topographically modified surface structure or surface structures form(s) one or more layers of dried-in agent or substance. 19. The implant as claimed in claim 4, characterized in that the bone-growth-stimulating and/or bone-growth-maintaining agent or agents on the topographically modified surface structure or surface structures form(s) one or more layers of dried-in agent or substance. 20. The implant as claimed in claim 5, characterized in that the bone-growth-stimulating and/or bone-growth-maintaining agent or agents on the topographically modified surface structure or surface structures form(s) one or more layers of dried-in agent or substance. |
Method for treating an implant, and such an implant |
The invention relates to a method for treating an implant, and to an implant treated by said method. All or some of the outer surfaces of the implant are oxidized with a layer (1a) of substantial thickness and substantial porosity or pore volume. One or more CaP layers (12) are applied to the porous surface or surface of large pore volume. Bone-growth-stimulating agents (13), for example rh-BMP-2 or rh-BMP-7, are then applied to the CaP layer. The method and the device make it possible to support a maximum quantity of bone-growth-stimulating agent, which can be controlled in respect of its release function. |
1. A method for further treating an implant (20) of tissue-compatible material, preferably titanium, and produced from a blank (19) of said material characterized in that: a) all or some of the outer surfaces of the implant are oxidized with a layer of substantial thickness, preferably with a thickness of more than 5 pin, and with a substantial porosity or pore volume, b) calcium phosphate compound(s) (CaP), preferably in the form of hydroxyapatite (HA), are applied to the porous surface, and c) bone-growth-stimulating agent/substance is then applied on the outside or on top of the calcium phosphate compound(s), preferably after the latter has or have been applied completely or dried completely. 2. The method as claimed in patent claim 1, characterized in that one or more first surfaces are provided with said oxide layers which are coated with either calcium phosphate compound(s) or said bone-growth-stimulating agents. 3. The method as claimed in patent claim 1, characterized in that one or more second surfaces are formed with said oxide layers which are coated with bone-growth-stimulating agents or said calcium phosphate compound(s), the first and second surfaces (32, 33) being given different structures/treatments. 4. An implant made of tissue-compatible material, preferably titanium, characterized by the following combination of elements: a) all or part of the outside of the implant is 5 provided with an oxide layer (ib) of substantial thickness and with a pore arrangement which has a substantial porosity or pore volume, b) one or more first layers or coatings of calcium phosphate compound or calcium phosphate compounds (Cap) are provided on the pore arrangement, and c) a second layer of bone-growth-stimulating agent/substance, preferably BMP, for example 15 rhBMP-2 or rhBMP-7, is provided on the pore arrangement, on top of said first layers. 5. The implant as claimed in patent claim 4, characterized in that the layer (2) of CaP, for example HA, has dual functions, namely, on the one hand, together with the porous and thick oxide layer, to form a depot or storage base for the layer of bone-growth-stimulating agent or substance lying on the outside, and, on the other hand, to participate in the bone-growth-stimulating function, the CaP layer preferably functioning with a longer time perspective than that which applies to the layer or layers of bone-growth-stimulating agent. 6. The implant as claimed in patent claim 4, characterized in that first surfaces which have said oxide layers are coated with either CaP or with bone-growth-stimulating agent. 7. The implant as claimed in patent claim 4, characterized in that second surfaces are coated with CaP or bone-growth-stimulating agent, and in that the oxide layer's combination with CaP or bone-growth-stimulating agent differs from the combination of the first surface or surfaces. 8. The implant as claimed in patent claim 4, characterized in that third surfaces do not have a porous oxidation layer and are coated with CaP and bone-growth-stimulating agent or with CaP or bone-growth-stimulating agent alone. 9. The implant as claimed in claim 4, characterized in that the oxide layer forms a main depot for CaP/HA and bone-growth-stimulating agent and the CaP/HA layer forms a subordinate anchoring depot for bone-growth-stimulating agent. 10. The implant as claimed in claim 4, characterized in that the CaP coating has a thickness within the range of a few Angstroms and 20 pm, and in that each bone-growth-stimulating agent layer has a thickness of between a few Angstroms and 1 rim. 11. The implant as claimed in claim 4, characterized in that the respective CaP layer constitutes a substantially amorphous CaP substance sputtered onto a CaP surface or implant surface which has a different degree of crystallinity by means of a subsequent heat treatment. 12. The implant as claimed in claim 4, characterized in that the CaP layer is formed with depressions which contribute to increasing the stability of bone-growth-stimulating agent in the CaP layer. 13. The implant as claimed in claim 4, characterized in that the CaP layer has a degree of crystallization of 25-75%. 14. The implant as claimed in claim 4, characterized in that the CaP layer or coating has a degree of crystallization of 75-100%. 15. The implant as claimed in claim 4, characterized in that layers with different degrees of crystallization are provided, and in that, in the case of three layers for example, the first layer has a degree of crystallization of 75-100%, the second layer has a degree of crystallization of 25-75%, and the third layer is amorphous. 16. The method as claimed in patent claim 2, characterized in that one or more second surfaces are formed with said oxide layers which are coated with bone-growth-stimulating agents or said calcium phosphate compound(s), the first and second surfaces (32, 33) being given different structures/treatments. 17. The implant as claimed in patent claim 5, characterized in that first surfaces which have said oxide layers are coated with either CaP or with bone-growth-stimulating agent. 18. The implant as claimed in patent claim 5, characterized in that second surfaces are coated with CaP or bone-growth-stimulating agent, and in that the oxide layer's combination with CaP or bone-growth-stimulating agent differs from the combination of the first surface or surfaces. 19. The implant as claimed in patent claim 6, characterized in that second surfaces are coated with CaP or bone-growth-stimulating agent, and in that the oxide layer's combination with CaP or bone-growth-stimulating agent differs from the combination of the first surface or surfaces. 20. The implant as claimed in patent claim 5, characterized in that third surfaces do not have a porous oxidation layer and are coated with CaP and bone-growth-stimulating agent or with CaP or bone-growth-stimulating agent alone. |
Method for forming light-absorbing layer |
A method of forming a light-absorbing layer of CIGS by first forming a thin-film precursor of Ib-IIIb group metals by sputtering and then treating by heat the precursor in a selenium atmosphere, wherein particles sputtered from an alloy target of Ib group-IIIb group metals and a single metal target of Ib group or IIIb group metal, disposed opposite to each other, are well mixed to form a thin single-layered precursor being free from the occurrence of reaction of metals at a boundary of layers. |
1. A light absorbing layer forming method of forming a thin-film precursor from Ib-IIIb group metals by a sputtering technique and by treating the formed precursor by heat in a selenium atmosphere to form a thin-film light-absorbing layer of CIGS, wherein the thin-film single-layered precursor is formed with well-mixed sputters from a pair of oppositely disposed targets one of which is an alloy carrier of Ib and IIIb group metals and the other is a single metal carrier of Ib group metal or IIIb group metal. 2. (Cancelled) 3. A light absorbing layer forming method as defined in claim 1, wherein the alloy of the Ib group metal and the IIIb group metal is of Cu—Ga or Cu A1 or In—Cu, the Ib group metal is Cu, and the IIIb group metal is In or A1. 4. A light absorbing layer forming method as defined in claim 1, wherein the thin-film single-layer precursor is formed by simultaneously sputtering the metals from the pair of oppositely disposed targets. 5. (Cancelled) 6. A light absorbing layer forming method as defined in claim 3, wherein the thin-film single-layer precursor is formed by simultaneously sputtering the metals from the pair of oppositely disposed targets. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to a light absorbing layer forming method. FIG. 1 shows a basic structure of a thin-film solar cell fabricated from a general compound semiconductor, which comprises a SLG (soda lime glass) substrate 1 on which a positive electrode layer (Mo) 2 , a light absorbing layer 4 , a buffer layer 5 (ZnS, Cds, etc.) and a transparent negative electrode layer (ZnO, Al, etc) are subsequently formed in the described order. In the compound semiconductor thin-film solar cell, the light absorbing layer 4 is a CIGS thin film formed of Cu (In+Ga) Se2 of the I-III-VI2 group based on Cu, (In, Ga), Se2, which possesses high power conversion efficiency exceeding 20%. The high quality CIGS thin layer having high power conversion efficiency can be formed by a vacuum evaporation method which, however, requires a substantial time to form layers and, therefore, decreases throughput of the products. A sputtering method may achieve high speed forming of a thin layer of CIGS with reduced times of supplying raw materials owing to the long life of each material target and with high reproducibility of quality of formed layers owing to the high stability of the targets themselves. This method, however, cannot obtain the CIGS thin layer having a power conversion efficiency comparable with that of the layer formed by a vacuum evaporation method. The reason for the above is explained by the fact that when forming a CIGS thin layer by sputtering at the same time as respective single metal targets (e.g., Cu, In and Se), negative ions sputtered mainly from the target Se cause damages by shock to the layer being formed, thus causing many defects in the CIGS thin layer formed (T. Nakada et al. “CuInSe2 Films for Solar Cells by Multi-Source Sputtering of Cu, In and Se—Cu Binary Alloy” Proc. 4th Photovoltaic Science and Engineering Conf. 1989, pp. 371-375). Consequently, the power conversion coefficient of a solar cell with a CIGS layer formed by sputtering Se reaches only a range of 6 to 8%. It has been reported that a CIGS thin layer was formed by depositing Se separately from other components to avoid the damage to the layer by negative ions of Se and a final product has attained a power conversion efficiency exceeding 10% (T. Nakada et al. “Micro-structure Characterization for Sputter-Deposited CuInSe2 Films and Photovoltaic Device” Jpn. Appl. Phys. 34, 1995, pp. 371-375). However, this method involves such a problem that a Cu target and an In target may be contaminated with vapor of Se and compounds such as CuSe and InSe are produced on their contaminated surfaces, resulting in unstable sputtering. There is known a conventional method of forming a light absorbing layer of CIGS, which is a so called selenization method by which a Se compound is formed by thermo-chemical reaction of a thin-film metal precursor with Se supplied from a source such as H2Se gas. U.S. Pat. No. 4798660 discloses a method in which a thin metal film with a metal back-electrode layer, a pure copper (Cu) single layer and a pure indium (In) single layer sequentially deposited thereon by a DC magnetron sputtering method is selenized in an atmosphere of Se (preferably in H2Se gas) to produce a light absorbing layer having a homogeneous composition of CIGS (copper indium diselenium). U.S. Pat. No. 4,915,745 discloses a method of forming a CIGS thin film by thermally treating a precursor laminated of a Cu—Ga alloy layer and a pure indium layer in the atmosphere of Se. In this instance, the Ga contained in the thin film of CIGS segregates to the Mo electrode layer, whereby the adhesion between the light absorbing layer and the Mo electrode layer is improved. This improves the performance of the solar cell using the CIGS layer. Japanese Laid-Open Patent Publication No. Hei-10-135495 describes a metal precursor which is formed by sputtering first with a target of Cu—Ga alloy and then with a target of pure indium. As shown in FIG. 2 , a thin firm of CIGS for a light absorbing layer 4 is formed on a Mo electrode layer 2 deposited on a SLG (soda lime glass) substrate 1 . Namely, a Cu—Ga metal thin layer 31 is first deposited on the Mo-electrode layer of the substrate by the first sputtering process SPT-1 using the Cu—Ga alloy target and then an In metal thin layer 32 on the Cu—Ga layer 31 by the second sputtering process SPT-2 using the In target to produce a metal-laminated precursor 3 ′ which is then treated by heat in the presence of Selenium (Se) gas to obtain a light absorbing film 4 in the form of a thin CIGS film. However, this precursor 3 ′ being a laminate of a Cu—Ga alloy layer 31 and a sole In layer 32 may be subjected to solid-state diffusion of elements which react with one another to form an alloy Cu—In—Ga at a boundary between the laminated layers both in process of forming the precursor and in the state of being temporarily stored. This reaction progresses during the selenization of the precursor. As it is difficult to evenly control the alloying reaction process between samples (requiring control of parameters relating to the alloying reaction, for example, temperature, time, etc), the quality of samples of the light absorbing layers 4 may vary considerably. The aggregation of indium is apt to occur, resulting in uneven composition in the layer. In Japanese laid-open Patent publication No. Hei-10-330936, there is disclosed an opposite target type sputtering apparatus for high-speed formation of films on a cooled substrate by using a pair of opposite targets of the same material, in which a space between the paired target is surrounded by a magnetic field to collect sputter plasma therein and deposit a film on the substrate disposed as facing to one of open sides of the space between the targets. The foregoing methods of manufacturing a light absorbing thin layer of CIGS by heat-treatment in a selenium atmosphere of a laminated precursor film formed in advance by sputtering Ib-IIIb group metals one after another involve a common problem of deterioration in quality of the finished product due to reaction of alloying elements at the boundary between the Cu—Ga layer and the In layer of the precursor, which reaction may progress through the manufacturing processes. |
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, an object of the present invention is to provide a method of forming a thin-film light absorbing layer by first forming a precursor film of Ib-IIIb group metals by sputtering and then treating by heat the precursor in an atmosphere of selenium to produce a thin-film of CIGS, wherein the precursor is formed by simultaneously sputtering from a pair of different metal targets disposed opposite to each other to deposit a mixture of sputtered particles on a Mo layer formed on a substrate. This precursor has a well mixed single-layered (not laminated) structure, which is free from alloying reaction of elements at a boundary of layers of a laminated precursor obtained by the conventional method. Another object of the present invention is to provide a method of forming a light absorbing layer of a solar cell, whereby a thin-film single-layered (i.e., not laminated) precursor is formed by simultaneously supplying Ib group metals and IIIb group metals and then subjected to heat-treatment in an atmosphere of selenium gas. The single-layered precursor can be free from the reaction of alloying elements at a boundary between layers of a laminated precursor obtained by the conventional method. |
Manufacturing device |
The present invention relates to a configurator and a method of configuring articles. A configurator regarded as a device of the type in question is a configurator comprising a processor having associated therewith a type-of-article memory, which has stored therein at least one data record representative of the outward appearance of a type of article, and an article design memory having stored therein data representative of a plurality of different article designs related with one type of article, an input unit for selecting a type of article and/or an article design, and a screen for displaying a predetermined, selected type of article with the selected article design. A configurator which is easier to construct and which allows the selected article design to be experienced directly is provided by the present invention in that a recognition means for recognizing a sample of the selectable article designs is provided, said recognition means detecting an article design signal which is representative of the article design and by means of which a specific article design is selected from the article design memory. |
1. A configurator for configuring articles, comprising a processor having associated therewith a type-of-article memory, which has stored therein at least one data record representative of the outward appearance of a type of article, and an article design memory having stored therein data representative of a plurality of different article designs related with one type of article, an input unit for selecting a type of article and/or an article design; a screen for displaying a predetermined or a selected type of article with the selected article design, and a recognition means for recognizing a selected sample of the selectable article designs, said recognition means detecting an article design signal which is representative of the article design and by means of which a specific article design corresponding to the sample is selected from the article design memory, characterized in that the recognition means comprises a receiver unit which is adapted to receive the article design signal of a transmitting unit associated with the selected sample, and that the transmitting unit and the receiver unit are adapted to one another in such a way that the article design signal of the sample selected from a plurality of samples presented to the user of the configurator will not be detected by the receiver unit until the selected sample has been transferred to a predetermined local area that is within reach of the user. 2. A configurator according to claim 1, characterized in that the receiver unit comprises a receiver plate, and that the transmitting unit is defined by a transponder which transmits the article design signal through energy supplied by said receiver plate. 3. A configurator according to claim 1, characterized in that the transmitting unit is adapted to be programmed. 4. A configurator according to claim 1, comprising a design element memory, which is associated with the processor and which has stored therein various selectable design elements, each of said design elements having associated therewith various designs in the article design memory, characterized in that the sample has associated therewith an element signal which is representative of the design element and by means of which a specific design element is selected from the design element memory. |
Use of tyrosine kinase inhibitors for treating autoimmune diseases |
The present invention relates to a method for treating autoimmune diseases, more particularly selected from the group consisting of multiple sclerosis, ulcerative colitis, Chron's disease, rheumatoid arthritis and polyarthritis, scleroderma, lupus erythematosus, dermatomyositis, pemphigus, polymyositis, vasculitis, as well as graft-versus host diseases, comprising administering a compound capable of depleting mast cells to a mammal in need of such treatment. Such compounds can be chosen from tyrosine kinase inhibitors and more particularly on-toxic, selective and potent c-kit inhibitors. Preferably, said inhibitor is unable to promote death of IL-3 dependent cells cultured in presence of IL-3. |
1. A method for treating autoimmune diseases comprising administering a compound capable of depleting mast cells to a mammal in need of such treatment. 2. A method according to claim 1 for treating autoimmune diseases comprising administering a tyrosine kinase inhibitor to a mammal in need of such treatment. 3. A method according to claim 2, wherein said tyrosine kinase inhibitor is unable to promote death of IL-3 dependent cells cultured in presence of IL-3. 4. A method according to claim 2 for treating autoimmune diseases comprising administering a c-kit inhibitor to a mammal in need of such treatment. 5. A method according to claim 4, wherein said c-kit inhibitor is a non-toxic, selective and potent c-kit inhibitor. 6. A method according to claim 5, wherein said inhibitor is selected from the group consisting of indolinones, pyrimidine derivatives, pyrrolopyrimidine derivatives, quinazoline derivatives, quinoxaline derivatives, pyrazoles derivatives, bis monocyclic, bicyclic or heterocyclic aryl compounds, vinylene-azaindole derivatives and pyridyl-quinolones derivatives, styryl compounds, styryl-substituted pyridyl compounds, seleoindoles, selenides, tricyclic polyhydroxylic compounds and benzylphosphonic acid compounds. 7. A method according to claim 5, wherein said inhibitor is selected from the group consisting of: pyrimidine derivatives, more particularly N-phenyl-2-pyrimidine-amine derivatives. indolinone derivatives, more particularly pyrrol-substituted indolinones, monocyclic, bicyclic aryl and heteroaryl compounds, and quinazoline derivatives. 8. A method according to claim 5, wherein said inhibitor is selected from the group consisting of N-phenyl-2-pyrimidine-amine derivatives having the formula II: Wherein R1, R2 and R3 are independently chosen from H, F, Cl, Br, I, a C1-C5 alkyl or a cyclic or heterocyclic group, especially a pyridyl group; R4, R5 and R6 are independently chosen from H, F, Cl, Br, I, a C1-C5 alkyl, especially a methyl group; and R7 is a phenyl group bearing at least one substituent, which in turn possesses at least one basic site, such as an amino function, preferably the following group: 9. A method according to claim 8, wherein said inhibitor is the 4-(4-méhylpipérazine-1-ylméthyl)N-[4-méthyl-3-(4-pyridine-3-yl)pyrimidine-2 ylamino)phényl)-benzamide. 10. A method according to one of claims 4 to 9, wherein said c-kit inhibitor is unable to promote death of IL-3 dependent cells cultured in presence of IL-3. 11. A method according to one of claims 4 to 10, wherein said c-kit inhibitor is an inhibitor of activated c-kit. 12. A method according to claim 11, wherein said inhibitor is capable of inhibiting constitutively activated-mutant c-kit. 13. A method according to claim 11, wherein said activated c-kit inhibitor is capable of inhibiting SCF-activated c-kit. 14. A method for treating autoimmune diseases comprising administering to a mammal in need of such treatment a compound that is a selective, potent and non toxic inhibitor of activated c-kit obtainable by a screening method which comprises: a) bringing into contact (i) activated c-kit and (ii) at least one compound to be tested; under conditions allowing the components (i) and (ii) to form a complex, b) selecting compounds that inhibit activated c-kit, c) testing and selecting a subset of compounds identified in step b), which are unable to promote death of IL-3 dependent cells cultured in presence of IL-3. 15. A method according to claim 14, wherein the screening method further comprises the step consisting of testing and selecting a subset of compounds identified in step b) that are inhibitors of mutant activated c-kit, which are also capable of inhibiting SCF-activated c-kit wild. 16. A method according to claim 14, wherein activated c-kit is SCF-activated c-kit wild in step a). 17. A method according to one of claims 14 to 17, wherein putative inhibitors are tested at a concentration above 10 μM in step a). 18. A method according to one of claims 14 to 18, wherein IL-3 is preferably present in the culture media of IL-3 dependent cells at a concentration comprised between 0.5 and 10 ng/ml, preferably between 1 to 5 ng/ml. 19. A method according to claim 18, wherein IL-3 dependent cells are selected from the group consisting of mast cells, transfected mast cells, BaF3 and IC-2. 20. A method according to one of claims 14 to 19, wherein the extent to which component (ii) inhibits activated c-kit is measured in vitro or in vivo. 21. A method according to one of claims 14 to 20, further comprising the step consisting of testing and selecting compounds capable of inhibiting c-kit wild at concentration below 1 μM. 22. A method according to claim 14 or 21, wherein the testing is performed in vitro or in vivo. 23. A method according to one of claims 14 to 22, wherein the inhibition of mutant-activated c-kit and/or c-kit wild is measured using standard biochemical techniques such as immunoprecipitation and western blot. 24. A method according to one of claims 14 to 23, wherein the amount of c-kit phosphorylation is measured. 25. A method according to one of claims 14 to 24, wherein identified and selected compounds are potent, selective and non-toxic c-kit wild inhibitors. 26. A method for treating autoimmune diseases comprising administering to a mammal in need of such treatment a c-kit inhibitor obtainable by a screening method comprising: a) performing a proliferation assay with cells expressing a mutant c-kit (for example in the transphosphorylase domain), which mutant is a permanent activated c-kit, with a plurality of test compounds to identify a subset of candidate compounds targeting activated c-kit, each having an IC50<10 μM, by measuring the extent of cell death, b) performing a proliferation assay with cells expressing c-kit wild said subset of candidate compounds identified in step (a), said cells being IL-3 dependent cells cultured in presence of IL-3, to identify a subset of candidate compounds targeting specifically c-kit, c) performing a proliferation assay with cells expressing c-kit, with the subset of compounds identified in step b) and selecting a subset of candidate compounds targeting c-kit wild, each having an IC50<10 μM, preferably an IC50<1 μM, by measuring the extent of cell death. 27. A method according to claim 26, wherein the extent of cell death is measured by 3H thymidine incorporation, the trypan blue exclusion method or flow cytometry with propidium iodide. 28. A method according to one of claims 1 to 27 for preventing and/or treating autoimmune diseases in human. 29. A method according to one of claims 1 to 27 for treating multiple sclerosis, psoriasis, subepidermal blistering disorders, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, proliferative glomerulonephritis, active chronic hepatitis, chronic fatigue syndrome and Vasculitis. 30. A method according to one of claims 1 to 27 for treating graft-versus-host disease or graft rejection in any organ transplantation including kidney, pancreas, liver, heart, lung, and bone marrow. 31. A method according to one of claims 1 to 27 for treating active chronic hepatitis and chronic fatigue syndrome. 32. A method according to one of claims 1 to 27 for treating Lupus erythematosis. 33. A method according to one of claims 1 to 27 for treating psoriasis and subepidermal blistering disorders including aphthous ulcers, and several bullous diseases such as Pemphigus vulgaris, Pemphigus vegetans, Pemphigus foliaceus, and Pemphigus erythematosus, bullous pemphigoid and cicatricial pemphigoid. 34. A method according to one of claims 1 to 27 for treating rheumatoid arthritis and polyarthritis. 35. A method according to one of claims 1 to 27 for treating Dermatomyositis. 36. A method according to one of claims 1 to 27 for treating ulcerative colitis and Crohn's disease. 37. A method according to one of claims 1 to 27 for treating multiple sclerosis. 38. Use of a c-kit inhibitor to manufacture a medicament for treating autoimmune diseases. 39. A composition suitable for topical administration comprising a compound capable of depleting mast cells, preferably a tyrosine kinase inhibitor, more particularly a c-kit inhibitor for the treatment of psoriasis, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, local and systemic scleroderna, dermatomyositis and Vasculitis. 40. A composition suitable for oral administration comprising a compound capable of depleting mast cells, preferably a tyrosine kinase inhibitor, more particularly a c-kit inhibitor for the treatment of multiple sclerosis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, myasthenia gravis, polymyositis, graft-versus-host disease, graft rejection, Graves disease, Addison's disease, autoimmune uveoretinitis, autoimmune thyroidiris, primary biliary cirrhosis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, proliferative glomerulonephritis, active chronic hepatitis, chronic fatigue syndrome and Vasculitis. 41. A composition suitable for intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, enteral, sublingual, or rectal administration comprising a compound capable of depleting mast cells, preferably a tyrosine kinase inhibitor, more particularly a c-kit inhibitor for the treating of autoimmune diseases. 42. A product comprising at least one compound capable of depleting mast cells, such as a tyrosine kinase inhibitors, more particularly a non-toxic, selective and potent c-kit inhibitor and at least one antibiotic, preferably selected from dapsone, azathioprine, erythromycin, propionylerythromycin, neomycin, gentomycin, tobramycin, and mechlocycline for simultaneous, separate or sequential use for the treatment of subepidermal blistering disorders, such as pemphigus. |
Novel indole derivatives |
A heteroaryl derivative having the formula (I). The compounds of the invention are considered useful for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders, and neurological disorders such as psychosis. |
1. A compound represented by the formula I wherein A represents O or S; n is 2,3,4,5,6,7, 8, 9 or 10; m is 2 or 3; W represents N, C or CH; Q represents N, C or CH; and the dotted line represents an optional bond; R1 represents hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl-C1-6-alkyl, aryl-C1-6-alkyl or acyl; R2, R3, R4, R5 and R6 independently represent hydrogen, halogen, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylsulfanyl, C1-6 alkylsulfonyl, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxycarbonyl, acyl, C3-8-cycloalkyl, C3-s-cycloalkyl-C1-6-alkyl, trifluoromethyl, trifluoromethoxy, NR15R16 wherein R15 and R16 independently represent hydrogen, C1-6-alkyl, C3-8-cycloalkyl or phenyl; or R15 and R16 together with the nitrogen to which they are attached form a 5- or 6-membered ring optionally containing one further heteroatom; R7 and R7′ independently represent hydrogen or C1-6-alkyl or may together form a bridge consisting of two or three methylene groups; R8, R9, R10 and R11 are each independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, thiophenyl, C1-6-alkoxy, C1-6-alkylsulfanyl, C1-6-alkylsulfonyl, hydroxy, formyl, acyl, acylamino, aminocarbonyl, C1-6-alkoxycarbonylamino, aminocarbonylamino, C1-6-alkylaminocarbonylamino and di(C1-6-alkyl)amino-carbonylamino, NR13R14 wherein R13 and R14 independently represent hydrogen, C1-6-alkyl, C3-8-cycloalkyl or phenyl; or R13 and R14 together with the nitrogen to which they are attached form a 5- or 6-membered ring optionally containing one further heteroatom; or an enantiomer or pharmaceutically acceptable acid addition salt thereof. 2. The compound according to claim 1, wherein n is 2, 3 or 4. 3. The compound according to claim 1, wherein W represents N. 4. The compound according to claim 1, wherein R7 and R7′ are both hydrogen. 5. The compound according to claim 1, wherein R1 is hydrogen. 6. The compound according to claim 1, wherein R2, R3, R4, R5 and R6 represent hydrogen. 7. The compound according to claim 1, wherein R8, R9, R10 and R11 independently represent hydrogen, halogen, C1-6-alkyl, C3-8-cycloalkyl, CN, CF3, OCF3, NH2, NR13R14 wherein R13 and R14 independently represent hydrogen, C1-6-alkyl, C3-8-cycloalkyl or phenyl; or R13 and R14 together with the nitrogen form a piperidine or pyrrolidine. 8. The compound according to claim 7, wherein R8, R9, R10 and R11 independently represent methyl, cyclopropyl, trifluoromethyl, cyano, chloro, bromo, piperidinyl, phenyl. 9. The compound according to claim 1, wherein said compound of formula I is a member selected from the group consisting of: 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile, 1a, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-(thiophen-2-yl)-4-trifluoromethylnicotinonitrile, 1b, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyridine, 1c, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinonitrile, 1d, 3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-chloropyridine, 1e, 3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-bromopyridine, 1f, 3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-2-methylpyridine, 1g, 3-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-5-chloropyridine, 1h, 2-{4-[4-(1H-Indol-4-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine, 1i, 2-{4-[4-(1H-Indol-4-yl)piperazin-1-yl]butylsulfanyl}-4,6-dimethylnicotinonitrile, 1j, 2-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propylsulfanyl}-5-trifluoromethylpyridine, 1k, 2-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propylsulfanyl}-4,6-dimethylnicotinonitrile, 1l, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinamide, 2a, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile, 2b, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methylpyridine, 2c, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-methyl-6-(piperidin-1-yl)nicotinonitrile, 2d, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethyl-6-cyclopropylnicotinonitrile, 2e, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-3-methanesulfonyl-4-methyl-6-phenylpyridine, 2f, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}nicotinonitrile, 2g, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-methylpyridine, 2h, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-6-methylnicotinamide, 2i, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-methyl-6-(piperidin-1-yl)nicotinonitrile, 2j, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-4-trifluoromethyl-6-cyclopropylnicotinonitrile, 2k, 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethoxy}-3-methanesulfonyl-4-methyl-6-phenylpyridine, 2l, 6-Chloro-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}4-methylnicotinonitrile, 2m, 6-Chloro-5-fluoro-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile, 2n, 4,6-Dimethyl-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine, 2o, 5-Cyano-4-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine, 2p, or 5-Cyano-4-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine, 2q, 5-Ethyl-2-{2-[4-(1H-indol-4-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine, 2r and 2-{2-[4-(1H-Indol-4-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethylpyrimidine, 2s. 10. A pharmaceutical composition comprising at least one compound according to claim 1 or claim 9, or a prodrug thereof, in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents. 11-13. (canceled) 14. A method for the treatment of a disorder or disease of a living animal body that is responsive to the effect of inhibition of serotonin uptake and antagonism of 5-HT1A receptors, comprising administering to such a living animal body a therapeutically effective amount of a compound according to claim 1 or claim 9. 15. A method for the treatment of a disorder or disease of a living animal body that is responsive to the effect of 5-HT1A and D4 receptors, comprising administering to such a living animal body a therapeutically effective amount of a compound according to claim 1 or claim 9. 16. A The method of treatment according to claim 14 where the disorder or disease is an affective disorder or a neurological disorder. 17. The method according to claim 14 wherein said animal body is a human body. 18. The method according to claim 14 wherein the administered compound is a pharmaceutically acceptable addition salt. 19. The method of claim 16 wherein said affective disorder is selected from the group consisting of general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders. 20. The method of claim 16 wherein said neurological disorder is psychosis. 21. The method of treatment according to claim 15 where the disorder or disease is an affective disorder or a neurological disorder. 22. The method according to claim 15 wherein said animal body is a human body. 23. The method according to claim 15 wherein the administered compound is a pharmaceutically acceptable addition salt. 24. The method of claim 21 wherein said affective disorder is selected from the group consisting of general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders. 25. The method of claim 21 wherein said neurological disorder is psychosis. 26. The compound according to claim 1 wherein the compound is a pharmaceutically acceptable addition salt of said compound of formula I. 27. The compound according to claim 9 wherein the compound is a pharmaceutically acceptable addition salt of said compound of formula I. 28. The composition according to claim 10 wherein said at least one compound is a pharmaceutically acceptable addition salt. |
<SOH> BACKGROUND ART <EOH>Clinical and pharmacological studies have shown that 5-HT 1A agonists and partial agonists are useful in the treatment of a range of affective disorders such as generalised anxiety disorder, panic disorder, obsessive compulsive disorder, depression and aggression. It has also been reported that 5-HT 1A ligands may be useful in the treatment of ischaemia. An overview of 5-HT 1A antagonists and proposed potential therapeutic targets for these antagonists based upon preclinical and clinical data are presented by Schechter et al. Serotonin 1997, Vol. 2, Issue 7. It is stated that 5-HT 1A antagonists may be useful in the treatment of schizophrenia, senile dementia, dementia associated with Alzheimer's disease, and in combination with SSRI antidepressants also to be useful in the treatment of depression. 5-HT reuptake inhibitors are well-known antidepressant drugs and useful for the treatment of panic disorders and social phobia. The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT 1A receptor antagonist has been evaluated in several studies mis, R. B. et al. Eur., J. Pharmacol. 1987, 143, p 195-204 and Gartside, S. E. Br. J. Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al. Trends Pharmacol. Sci. 1994, 15, 220). In these studies it was found that combined 5-HT 1A receptor antagonists and serotonin reuptake inhibitors would produce a more rapid onset of therapeutic action. Dopamine D 4 receptors belong to the family of dopamine D 2 -like receptors which is considered to be responsible for the antipsychotic effects of neuroleptics. Dopamine D 4 receptors are primarily located in areas of the brain other than striatum, suggesting that dopamine D 4 receptor ligands have antipsychotic effect and are devoid of extrapyramidal activity. Accordingly, dopamine D 4 receptor ligands are potential drugs for the treatment of psychosis and positive symptoms of schizophrenia and compounds with combined effects at dopamine D 4 , and serotonergic receptors may have the further benefit of improved effect on negative symptoms of schizophrenia, such as anxiety and depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia and cardiovascular disorders and in the improvement of sleep. Dopamine D 3 receptors also belong to the family of dopamine D 2 -like receptors. D 3 antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to EPS and hormonal changes. Accordingly, agents acting on the 5-HT 1A receptor, both agonists and antagonists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired. Furthermore, antagonists, at the same time having potent serotonin reuptake inhibition activity and/or D 4 and/or D 3 activity, may be particularly useful for the treatment of various psychiatric and neurological diseases. Previously, closely related structures have been reported: WO 9955672 discloses a general formula in which indole derivatives having 5-HT 1A receptor and D 2 receptor affinity are included EP 900792 discloses a general formula in which indole derivatives are embraced as 5-HT 1A and 5-HT 1D as well as D 2 receptor ligands. It has now been found that a class of indole derivatives is particularly useful as 5-HT 1A ligands. Furthermore, it has been found that many of these compounds have other highly beneficial properties as e.g. potent serotonin reuptake inhibition activity and/or affinity for the D 4 receptor. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention comprises the following: A compound represented by the general formula I wherein A represents O or S; n is 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 2 or 3; W represents N, C or CH; Q represents N, C or CH; and the dotted line represents an optional bond; R 1 represents hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl-C 1-6 -alkyl or acyl; R 2 , R 3 , R 4 , R 5 and R 6 independently represent hydrogen, halogen, cyano, nitro, C 1-6 -alkyl, C 1-6 alkoxy, C 1-6 -alkylsulfanyl, C 1-6 alkylsulfonyl, hydroxy, hydroxy-C 1-6 -alkyl, C 1-6 alkoxycarbonyl, acyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-4 -alkyl, trifluoromethyl, trifluoromethoxy, NR 15 R 16 wherein R 15 and R 16 independently represent hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or phenyl; or R 15 and R 16 together with the nitrogen to which they are attached form a 5- or 6-membered ring optionally containing one further heteroatom; R 7 and R 7′ independently represent hydrogen or C 1-6 -alkyl or may together form a bridge consisting of two or three methylene groups; R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, phenyl, thiophenyl, C 1-6 -alkoxy, C 1-6 -alkylsulfanyl, C 1-6 -alkylsulfonyl, hydroxy, formyl, acyl, acylamino, aminocarbonyl, C 1-6 -alkoxycarbonylamino, aminocarbonylamino, C 1-6 -alkylaminocarbonylamino and di(C 1-6 -alkyl)aminocarbonylamino, NR 13 R 14 wherein R 13 and R 14 independently represent hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or phenyl; or R 13 and R 14 together with the nitrogen to which they are attached form a 5- or 6-membered carbocyclic ring optionally containing one further heteroatom; its enantiomers, and a pharmaceutically acceptable acid addition salt thereof. The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent. In a further embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin uptake and antagonism of 5-HT 1A receptors. In a further embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the combined effect of 5-HT 1A receptors and dopamine D 4 receptors. In particular, the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders; other psychiatric disorders such as psychosis and neurological disorders. In still another embodiment, the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the inhibition of serotonin uptake and antagonism of 5-HT 1A receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. In still another embodiment, the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the effect of 5-HT 1A and D 4 receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. Due to their combined antagonism of 5-HT 1A receptors and serotonin reuptake inhibiting effect, the compounds of the invention are considered particularly useful as fast onset of action medicaments for the treatment of depression. The compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants. The compounds of the invention have high affinity for the 5-HT 1A and D 4 receptors. Accordingly, the compounds of the invention are considered useful for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders; other psychiatric disorders such as psychosis and neurological disorders. detailed-description description="Detailed Description" end="lead"? |
Sensor for determining radiated energy and use thereof |
The invention relates to a sensor for determining the energy of radiation of a type that is capable of converting oxygen into ozone, and to a use of such a sensor. According to the invention, the sensor contains a measuring chamber (1) that can be transirradiated by the radiation and has a gas inlet (4) and a gas outlet (6), means (8) for feeding an oxygen containing gas (9) into the measuring chamber, via the gas inlet, and for discharging the gas via the gas outlet, one ozone sensor element (10) for measuring the ozone content of the gas (9a) located in the measuring chamber or discharged via the gas outlet, and evaluating means (12) for determining the radiant energy from the measured ozone content. The sensor can be used, for example, to determine radiant energy in an optical imaging system operating with the radiation. Use, for example, in microlithography projection exposure systems. |
1. A sensor for determining the energy of radiation of a type that is capable of converting oxygen into ozone, characterized by a measuring chamber (1) that can be transirradiated by the radiation (12) and has a gas inlet (4) and a gas outlet (6), means (8) for feeding an oxygen containing gas (9) into the measuring chamber, via the gas inlet, and for discharging the gas via the gas outlet, at least one ozone sensor element (10) for measuring the ozone content of the gas (9a) located in the measuring chamber or discharged via the gas outlet, and evaluating means (12) for determining the radiant energy from the measured ozone content. 2. The sensor as claimed in claim 1, further characterized in that the measuring chamber is formed by a rectilinear measuring tube (1) that can be traversed by the radiation (12) in a longitudinal direction. 3. The sensor as claimed in claim 1 or 2, further characterized in that the gas inlet (4) and the gas outlet (6) are located at opposite end regions of the measuring chamber (1). 4. The sensor as claimed in one of claims 1 to 3, further characterized in that the ozone sensor element (10) is arranged in the region of the gas outlet (6) or of a gas outlet line (7) leading away from said outlet. 5. The sensor as claimed in one of claims 1 to 4, further characterized in that the gas feeding means (8) are set up for variable setting of the feed rate and/or of the oxygen concentration of the oxygen containing gas. 6. A use of the sensor as claimed in one of claims 1 to 5, for determining the radiant energy in an optical imaging system operating with the radiation (12). |
Energy applicators adapted to dielectric heating |
A dielectric heating system with which the power density applied to the product being treated can be at least doubled without risk of electric arcs. This invention is particularly suitable for treatment of compounds that absorb electromagnetic waves weakly (low dielectric constants). In particular, fatty substances such as oils, butters, waxes and fats can be treated (refining, hydrolysis, transesterification, interesterification, etc.), derivatives thereof (esterification, polymerization, alcoholysis, ethoxylation, hydrogenation, etc.) under static or dynamic conditions, as can hydrocarbons and aromatic compounds. This system can also be used advantageously for polar or polarized compounds, because the power absorbed is increased very significantly, with large production gains. In particular, fatty or non-fatty alcohols (oleic alcohol, glycol, glycerol, mannitol, sorbitol, polyglycerols, vitamins, etc.), carboxylic acids, amines and similar compounds can be treated under static or dynamic conditions. |
1 An energy applicator, of the type comprising a waveguide and lateral chimney members, for dielectric heating of any compound, at microwave frequencies or high frequencies, under static or dynamic conditions, with relative power density higher than that of the usual applicators, without risk of electric arcs or “discharge”, regardless of the dielectric constants of the said compound, characterized in that the said applicator is provided with at least one resonant cavity that extends around the waveguide, for treatment of the product. 2 An energy applicator, of the type comprising a waveguide and lateral chimney members, for dielectric heating of any compound, at microwave frequencies or high frequencies, under static or dynamic conditions, at relative power density higher than that of the usual applicators, without risk of electric arcs or “discharge”, regardless of the dielectric constants of the said compound, characterized in that the said applicator is provided with at least one chimney member of geometry adapted to form a resonant cavity around the waveguide, for treatment of the product under consideration, 3 An applicator according to claim 1 or 2, characterized in that this cavity is formed on each side of the waveguide. 4 An applicator according to claim 1 or 2, characterized in that this cavity is formed around the waveguide by one or more chimney members. 5 An applicator according to claim 4, characterized in that the chimney member or chimney members is or are placed on each side of the waveguide, around the resonant cavity. 6 An applicator according to any one of claims 1 to 5, characterized in that the shape of the said cavity formed around the waveguide is chosen from among: the symmetric shapes, the shapes composed of at least a conical base, a spherical shape or a shape of ellipsoidal volume, the broadest portion opening into the waveguide. 7 An applicator according to any one of claims 4 to 6, characterized in that it contains a plurality of chimney members of identical geometry. 8 An applicator according to any one of claims 4 to 7, characterized in that the chimney members are composed of two main portions: an upper portion, which must be as close as possible to the reactor in order to prevent waves from leaking out, and a lower portion whose shape flares toward the waveguide to prevent electric arcs. 9 An applicator according to claim 8, characterized in that the upper portion of the chimney members must be as close as possible to the reactor in order to prevent leakage of waves, and it can have cylindrical shapes with circular, rectangular or square cross section. 10 An applicator according to claim 9, characterized in that the chimney members have a geometry composed of different successive shapes. 11 An applicator according to claim 9 or 10, characterized in that the upper portion of the chimney members has a cylindrical shape with circular cross section, in order to conform best to the shape of the reactor and to avoid the presence of edges, which favor electric arcs. The height of this portion of the chimney member is determined so as to exclude any leakage of waves. 12 An applicator according to claim 9 or 10, characterized in that the lower portion of these chimney members, or in other words that close to the waveguide, is of flared shape. 13 An applicator according to claim 12, characterized in that the said shape is chosen from among the conical and/or spherical shapes having variable angles relative to the vertical, and from the pyramidal shapes having square or rectangular bases. 14 An applicator according to claim 12 or 13, characterized in that the base diameter of these flared shapes must not exceed the width of the waveguide, and then the height and apex angle of the flared portion are fixed as a function of the power used. 15 Applicators according to any one of claims 1 to 14, characterized in that there are used single-mode microwave applicators at 2450 MHz, and in that the recommended waveguide width for remaining in TE 0.1 mode (transverse electric) ranges between approximately 70 and 100 mm, the TE 0.1 fundamental mode of excitation permitting the wave to propagate along a single arc. 16 Applicators according to any one of claims 1 to 15, characterized in that there are used applicators operating at other microwave frequencies and at high frequencies. 17 Applicators according to any one of claims 1 to 16, characterized in that the chimney members comprise an upper standard cylindrical portion and a lower conical portion at the waveguide. 18 Applicators according to any one of claims 1 to 17, characterized in that there are used high-frequency applicators chosen from among the following: applicators of capacitive type, formed from two capacitor foils between which there is applied the high-frequency voltage of the generator, the said applicators being used for heat treatment of materials whose volume comprises a parallelepiped in which one of the sides is sufficiently thick (>10 mm), rod applicators for flat materials, comprising tubular or rod electrodes, the said applicators being used for heat treatment of materials whose volume comprises a parallelepiped in which one of the sides is not sufficiently thick (<10 mm), applicators for thread-like materials, formed of loops. microwave applicators, chosen from among: localized-field applicators: single-mode cavity, diffuse-field applicators: multimode cavity, near-field applicators: radiating-antenna guide. 19 Applicators according to any one of claims 1 to 18, characterized in that a resonant microwave system is created by means of a localized-field or a diffuse-field applicator. 20 An applicator according to claim 19, characterized in that it creates a “single-mode” system (localized field), which is formed from single-mode cavities resonating at the emission frequency along a beam in the direction of the guide. 21 An applicator according to claim 19, characterized in that it creates a “multimode” system (diffuse field). 22 An applicator according to any one of claims 4 to 21, characterized in that the length of each chimney member is determined so as to exclude any leakage of waves and to comply with the safety measures relating to personnel and telecommunications. 23 Chimney members for energy applicators for dielectric heating of any compound at microwave frequencies or high frequencies, under static or dynamic conditions, with high power density, without risk of electric arcs or “discharge”, regardless of the dielectric constants of the said compound, characterized in that the said chimney members are such as described in any one of claims 1 to 22. 24 Use of the applicators or chimney members according to any one of claims 1 to 22 or 23 for application of microwave or high-frequency electromagnetic waves for heating applications on compounds that absorb the radiation weakly and on compounds having high dielectric constants (∈′>5 and ∈″>0.5). 25 Applications according to claim 24 for performing heat treatments on compounds that absorb electromagnetic waves weakly or on polar or polarized compounds. 26 Applications according to claim 24 or 25 for the treatment of fatty acid esters (unsaturated or otherwise), of hydrocarbons (unsaturated or otherwise), of aromatic compounds and of derivatives of the latter, and of products that absorb electromagnetic waves, to increase the production capacity of a given system (fatty and non-fatty alcohols, carboxylic acids, amines, etc.), and for all reactions of “lipochemistry”, with in particular a very strong interest for the case of products that absorb electromagnetic waves weakly, such as for isomerization of fatty acids or of esters of monounsaturated or polyunsaturated fatty acids, or of waxes, and in particular of castor oil. 27 Applications according to any one of claims 24 to 26, characterized in that there are achieved all the heating applications involving a single reactant or a mixture of reactants in variable proportions, such as esterification, transesterification, epoxidation, sulfatization, phosphatization, amidification, polymerization and polycondensation reactions as well as decolorization, deodorization and the systems for elimination of volatile compounds. 28 Applications according to any one of claims 24 to 28 for synthesis of polymers of unsaturated fatty acids, of esters of unsaturated fatty acids, of unsaturated hydrocarbons or of derivatives of such products by means of dielectric heating with microwaves. 29 Applicators according to any one of claims 24 to 28, characterized in that there are used chemical agents chosen from among the following: Reactants: the products that absorb electromagnetic waves weakly or the products that absorb strongly or a mixture of the two, with or without additions of catalysts or weakly or strongly absorbing additives, strongly absorbing products: the fatty or non-fatty alcohols, fatty or non-fatty amines, carboxylic acids, acetals, ketones, enols, peracids, epoxides and chemical compounds containing a polar or polarized function, as alcohols: sorbitol, glycerol, mannitol, glycols, vitamins (such as tocopherol, ascorbic acid, retinol), polyphenols, sterols (including the phytosterols) and as amines: ammonia, primary, secondary and tertiary alkylamines (methylamine, dimethylamine, trimethylamine, diethylamine), the fatty amines (oleic amines, alkylamines of coconut oil), the aminoalcohols (monoethanolamine MEA, diethanolamine DEA, triethanolamine TEA; 3-amino-1,2-propanediol, 1-amino-2-propanol) and ethoxylated amines (2,2′-aminoethoxyethanol; amino-1-methoxy-3-propane), saturated or unsaturated, straight-chain or branched, catalysts or additives: the acid catalysts such as paratoluenesulfonic acid, sulfuric acid, phosphoric acid, perchloric acid, etc., the basic catalysts such as sodium hydroxide, potassium hydroxide, alkali metal and alkaline earth alcoholates, sodium acetate, triethylamines, pyridine derivatives, etc., the acid and/or basic resins of the Amberlite™, Amberlyst™, Purolite™, Dowex™ and Lewatit™ type, zeolites, enzymes and carbon blacks, weakly absorbing products: the animal or vegetable oils and fats and the polyterpenes, some of which are derived from the said oils and fats, oils or fats of animal origin: sperm oil, dolphin oil, whale oil, seal oil, sardine oil, herring oil, shark oil, cod-liver oil, neatsfoot oil and beef, pork, horsemeat and mutton fats (suets), oils of vegetable origin: rapeseed oil, sunflower-seed oil, peanut oil, olive oil, walnut oil, corn oil, soybean oil, linseed oil, hemp oil, grape-seed oil, coconut oil, palm oil, cottonseed oil, babassu oil, jojoba oil, sesame oil, castor oil, dehydrated castor oil, hazelnut oil, wheat-germ oil, borage oil, onager oil and tall oil, components of animal or vegetable oils: squalene, extracted from the unsaponifiable fractions of vegetable oils (olive oil, peanut oil, rapeseed oil, corn-germ oil, cottonseed oil, linseed oil, wheat-germ oil, rice-bran oil), or the squalene contained in shark oil, the said oils and fats of animal or vegetable origin as well as the derivatives thereof being capable of being subjected to a preliminary treatment aimed at making them more reactive or, on the other hand, less reactive, unsaturated hydrocarbons: an alkene, such as a terpenoid hydrocarbon or hydrocarbons, meaning a polymer or polymers of isoprene, or a polymer or polymers of isobutene, styrene, ethylene, butadiene, isoprene or propene, or a copolymer or copolymers of these alkenes, individually or in mixtures, monounsaturated or polyunsaturated fatty acids or fatty acid esters, waxes, castor oil. |
<SOH> TECHNICAL FIELD OF THE INVENTION AND PROBLEM POSED <EOH>The present invention relates to the design and use of energy applicators, and more particularly to resonant cavities and chimney members of shapes and dimensions adapted to the dielectric heating of any compound, regardless of the dielectric constants thereof. The usual microwave and high-frequency applicators are equipped with traditional chimney members that make it impossible to work at high power density without the risk of electric arcs. The purpose of the chimney members used by the person skilled in the art is aimed at subjecting a product (liquid, solid, gaseous or a mixture of the three states) to electromagnetic waves under static or dynamic conditions, while preventing waves from leaking out of the waveguide. The chimney members, of traditional shape, preferably of cylindrical shape, make it impossible to reach the desired temperature level rapidly and/or to treat a larger quantity of product without the risk of electric arcs. In contrast to polar or polarized molecules, for which energy transfer is optimum, a high power density proves to be necessary to achieve heating of compounds, characterized by low dielectric constants, that absorb electromagnetic waves weakly. Thus there exists a serious technical problem, posed by the risks of “discharge” or electric arcs and the industrial consequences thereof, which problem represents a major concern in industry, because of the importance of the industrial applications indicated here. By virtue of the invention, the time for processing the products can be very greatly shortened and, in parallel, the industrial efficiency can be improved. |
<SOH> SUMMARY OF THE INVENTION <EOH>After numerous attempts, the Applicant has discovered a new shape or geometry for the chimney member, in particular a chimney member of conical shape or geometry, that makes it possible to heat any type of product at microwave frequencies or high frequencies under static or dynamic conditions with a high power density without risk of electric arcs or “discharge”. |
Tape guide device for gardening buncher |
A rib (206c) is formed on a ceiling surface of a tape guide mounted on a driver handle of a binding machine for gardening, and two plate springs (224a, 224b) are mounted on the bottom plate portion of the tape guide. The plate spring (224a), which is situated on the downstream side, is elastically contacted with the rib (206c) to thereby allow the plate spring (224a) and rib (206c) to hold tape (T) between them, while the upstream-side plate spring (224b) is contacted with the tape. When a tape roll is rotated reversely and the tape is thereby pulled back, tension is applied to the tape existing between the rib (206c) and tape roll, and the upstream-side plate spring (224b) is raised up due to the friction of the tape to curve a passage of the tape, which increases the frictional resistance of the tape to thereby be able to prevent the tape (T) against reverse movement. |
1. A tape guide apparatus in a binding machine for gardening, comprising: a driver handle; a tape magazine storing tape and disposed on said driver handle; a tape guide mounted on said driver handle for forming a cylindrical tape passage upwardly of said driver handle; a clincher arm disposed in combination with said driver handle; a first projecting portion formed on an inner wall surface of said tape passage; a first plate spring disposed on the inner wall surface of said tape passage opposed to said first projecting portion, having a leading end thereof directed toward the downstream side of said tape passage, and elastically contactable with said first projecting portion; and a second plate spring disposed on the inner wall surface of said tape passage opposed to said first projecting portion, arranged in series with said first plate spring, and having a leading end thereof directed toward the downstream side of said tape passage, wherein said tape loaded into said tape magazine is inserted into said tape passage and is pulled out from the leading end portion of said tape guide, and wherein said tape is held by and between said first plate spring and said first projecting portion, and said second plate spring is contacted with said tape to apply pull-back resistance to said tape, thereby preventing said tape against reverse movement. 2. The tape guide apparatus in a binding machine for gardening as set forth in claim 1, further comprising: a fixing stopper mounted so as to extend from the base portion to a middle portion of said second plate spring for restricting the oscillation angle of said second plate spring. 3. The tape guide apparatus in a binding machine for gardening as set forth in claim 1, further comprising: a second projecting portion formed on the inner wall surface of said tape guide and arranged in series with said first projecting portion, wherein said second plate spring can be elastically contacted with said second projecting portion, and wherein said tape is held by and between said second plate spring and said second projecting portion to apply pull-back resistance to said tape, thereby preventing said tape against reverse movement. 4. The tape guide apparatus in a binding machine for gardening as set forth in claim 1, wherein said first plate spring and said second plate spring are an integrated plate spring of two long and short plate springs produced by working a U-shaped cut in a single plate spring. 5. The tape guide apparatus in a binding machine for gardening as set forth in claim 1, wherein the tip end of said second plate spring is formed so as to have an angular shape or a notch-like shape. 6. The tape guide apparatus in a binding machine for gardening as set forth in claim 1, wherein said tape guide is formed so as to have a cylindrical shape. 7. A tape guide apparatus in a binding machine for gardening, comprising: a driver handle; a tape magazine storing tape therein and disposed on said driver handle; a tape guide including a tape pull-out opening in a leading end thereof and disposed on said driver handle; a clincher arm disposed in combination with said driver handle; a tape clamp device disposed on said clincher arm for clamping a leading end portion of said tape inserted through said tape guide and pulled out from said tape pull-out opening to pull out said tape from said tape magazine; and a plate spring mounted within said tape guide so as to face forwardly, for pressing said tape against the inner wall surface of said tape guide to thereby apply pull-out tension to said tape, wherein not only the tip end of said plate spring is elastically contacted with the upper or lower wall surface of said tape guide existing in the vicinity of the front end of said tape guide but also the contact point of said plate spring and said tape pull-out opening are respectively shifted up and down to curve a passage of said tape at a sharp angle, thereby preventing said tape against reverse movement. |
<SOH> BACKGROUND ART <EOH>In the cultivation of creeping plants such as a grape, a cucumber, a melon and a tomato, in an operation to bind the vines or branches of these creeping plants along support posts or trellises, there is used a binding machine for gardening. The binding machine for gardening is a tool of a hand-held stapler type which is a combination of a driver handle and a clincher arm, while a tape magazine is mounted on the rear portion of the driver handle. To use the binding machine for gardening, tape loaded into the tape magazine is pulled out from a tape pull-out opening formed in the leading end portion of the driver handle. When the driver handle and clincher arm are closed once, the leading end of the tape is caught by a tape clamp device which is disposed on the clincher arm. Then, when the driver handle and clincher arm are opened, the tape is strung between the driver handle and clincher arm. Further, when the tape is wound around the branches of the plant and posts and then the driver handle and clincher arm are closed with a stronger force than the previous time, the overlapped portion of the tape wound around the branches is bound and, at the same time, the cutter blade cuts the tape in the vicinity of the bound portion, thereby separating the tape loop wound around the branches from the tape main body. When binding the plant, an operator uses the binding machine for gardening at various attitudes; and, due to the varying attitudes, in some cases, the tape roll existing within the tape magazine can be rotated reversely and thus the leading end of the tape can be pulled back into the driver handle. In this case, there is a possibility that the tape grip device on the clincher arm side cannot catch the leading end of the tape on the driver handle side and thus fails to bind the plant; and, the leading end of the tape must be pulled to adjust the tape pull-out amount of the tape, which takes time and labor. In a conventional binding machine for gardening, a plate spring is disposed within the driver handle, and the tape is pushed against the wall surface of a tape passage or against a guide by the plate spring to apply pull-out tension to the tape, thereby preventing the tape from loosening. However, since the reversing preventive action is weak, the reverse movement of the tape occurs frequently. Thus, in order to prevent the reverse movement of the tape, there arise technical problems to be solved. Accordingly, it is an object of the invention to solve the above problems. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a side view of a binding machine for gardening, showing a first embodiment according to the invention. FIG. 2 is a section view of the front portion of a binding machine for gardening. FIG. 3 is a section view of a binding machine for gardening, showing a state thereof in which a tape loop is formed. FIG. 4 is a section view of the front portion of a driver handle, showing a tape guide apparatus according to the invention. FIG. 5 is a section view of the front portion of the driver handle when a tape is pulled out. FIG. 6 is a side view of a binding machine for gardening, showing a second embodiment according to the invention. FIG. 7 is a side section view of a binding machine for gardening, showing its operation process. FIG. 8 is a side section view of a binding machine for gardening, showing its operation process. FIG. 9 is a side section view of a binding machine for gardening, showing its operation process. FIG. 10 is a side section view of a binding machine for gardening, showing its operation process. FIG. 11 is a side section view of a binding machine for gardening, showing its operation process. FIG. 12 is a side section view of a binding machine for gardening, showing its operation process. FIG. 13 is a side section view of the front portion of the driver handle. FIGS. 14 ( a ) and 14 ( b ) respectively show a plate spring; specifically, FIG. 14 ( a ) is a plan view of the plate spring and FIG. 14 ( b ) is a side view thereof. FIG. 15 is a side section view of the front portion of the driver handle. FIG. 16 is a side section view of the front portion of the driver handle. FIG. 17 is a side section view of the front portion of the driver handle. FIGS. 18 ( a ) and 18 ( b ) respectively show a plate spring; specifically, FIG. 18 ( a ) is a plan view of the plate spring and FIG. 18 ( b ) is a side view thereof. FIGS. 19 ( a ) and 19 ( b ) respectively show a plate spring; specifically, FIG. 19 ( a ) is a plan view of the plate spring and FIG. 19 ( b ) is a side view thereof. FIG. 20 is a broken view of the front portion of a driver handle. FIG. 21 is a side section view of the front portion of a driver handle used in a binding machine for gardening according to a third embodiment of the invention. FIG. 22 is a side section view of the front portion of a driver handle used in a binding machine for gardening according to a fourth embodiment of the invention. In the drawings, reference character 101 designates a binding machine for gardening, 102 a driver handle, 103 a clincher arm, 104 a lower handle, 105 a tape magazine, 106 a clincher, 107 a picking plate, 108 a push plate, 109 a tape support plate, 110 a staple driver, 111 a staple magazine, 112 a cutter blade, 113 a handle frame, 114 a handle cover, 115 a tape pull-out opening, 116 a plate spring, 201 a binding machine for gardening, 202 a driver handle, 203 a clincher arm, 204 a lower handle, 206 a tape guide, 206 c a rib, 207 a staple magazine, 210 a cutter blade, 211 a driver, 212 a clincher, 213 a picking plate, 215 a tape support plate, 224 a plate spring, 224 a a long spring portion, 24 b a short spring portion, and T tape, respectively. detailed-description description="Detailed Description" end="lead"? |
Method for processing ginseng and the uses of extract of processed ginseng |
The present invention relates to a method of processing ginseng and the uses of the extract of processed ginseng. More particularly, the present invention relates to extract of the processed ginseng which can improve the ratio of ginsenoside (Rg3+Rg5)/(Rb1+Rb2+Rc+Rd) to 10-45 due to a synergy effect by mixing ginseng with herbal drugs such as Schizandrae Fructus, Crataegi Fructus, Corni Fructus, Chaenomelis Fructus, Mume Fructus, Citrus junos, Aurantii Fructus, apples, Fructus of Punica granatum and Citrus limon, extract of saponin fraction of the processed ginseng, and a method of processing ginseng via heat treatment of the mixture of ingredients comprising the mixture of ingredients comprising ginseng and the aforementioned herbal drug(s) at a temperature of 70-120° C. |
1-13. cancelled 14. An extract of a processed ginseng having a ratio of ginsenoside (Rg3+Rg5)/(Rb1+Rb2+Rc+Rd) of 10-45. 15. The extract of claim 14, wherein the ratio of ginsenoside (Rg3+Rg5)/(Rb1+Rb2+Rc+Rd) is 20-45. 16. The extract of claim 14, wherein the ratio of ginsenoside is determined as a relative peak area by HPLC. 17. An extract of saponin fraction of a processed ginseng having a ratio of ginsenoside (Rg3+Rg5)/(Rb1+Rb2+Rc+Rd) of 10-45. 18. The extract of claim 17, wherein the ratio of ginsenoside (Rg3+Rg5)/(Rb1+Rb2+Rc+Rd) is 20-45. 19. The extract of claim 17, wherein the ration is determined as a relative peak area by HPLC. 20. A method of processing ginseng by heat-extraction, comprising the steps of: (i) adding about 4-10 times weight of water to the mixture consisting of about 100 parts of ginseng and about 10-1000 parts of at least one herbal drug selected from the group consisting of Schizandrae Fructus, Crataegi Fructus, Corni Fructus, Chaenomelis Fructus, Mume Fructus, Citrus junos, Aurantii Fructus, apples, Fructus of Punica granatum and Citrus limon, and heating for about 1-6 hours at about 70-120° C.; (ii) cooling said mixture to room temperature and filtering said mixture to form a filtrate; and (iii) concentrating said filtrate to form an extract or powder. 21. The method of claim 20, which further comprises a step of heat-extracting, following step (i), wherein said water is evaporated and a remaining mixture is heated for 1-3 hours in the presence of ethanol or methanol. 22. The method of claim 20, which ginseng is selected from the group consisting of white ginseng, fresh ginseng, hairy root ginseng, red ginseng, ginseng leaves of Panax ginseng, Panax quinquelifolium, Panax notoginseng and Panax japonicus. 23. A pharmaceutical composition comprising the extract of processed ginseng of claim 1, and a carrier. 24. A pharmaceutical composition comprising the extract of saponin fraction of processed ginseng of claim 17, and a carrier. 25. The pharmaceutical of composition claim 23, which is in a form selected from the group consisting of liquids, tablets, granules, pills, hard capsules, and soft capsules. 26. The pharmaceutical composition of claim 24, which is in a form selected from the group consisting of liquids, tablets, granules, pills, hard capsules, and soft capsules. 27. A food additive comprising an extract of the processed ginseng of claim 23. 28. A food additive comprising an extract of the saponin fraction of the processed ginseng of claim 24. 29. A health supplementary food comprising the extract of the processed ginseng claim 23 in a food. 30. A healthy supplementary food comprising the extract of saponin fraction of the processed ginseng of claim 24 in a food. 31. The healthy supplementary food of claim 29, which is a beverage. 32. The healthy supplementary food of claim 30, which is a beverage. 33. A method of improving blood circulation in a mammal, which comprises administering to the mammal an effective amount of the processed ginseng of claim 14, or claim 17, to a mammal in need thereof. 34. The method of claim 33, wherein said improved blood circulation ameliorates erectile dysfunction. 35. The method of claim 33, wherein said improved blood circulation ameliorates hypertension. 36. The method of claim 33, wherein said improved blood circulation ameliorates arteriosclerosis. 37. The method of claim 33, wherein said improved blood circulation ameliorates antithrombosis. 38. The method of claim 33, wherein said improved blood circulation ameliorates cerebral function. 39. The method of claim 33, wherein said improved blood circulation ameliorates cerebral apoplexy. 40. The method of claim 33, wherein said mammal is a human. |
<SOH> BACKGROUND ART <EOH>Ginseng is a globally well-known nourishing tonic. Therefore, extensive studies have been carried out to identify and characterize its constituents as well as its pharmacological actions of the constitutents. These studies have revealed that the ginseng has a variety of thereapeutic effects such as preventing aging process and arteriosclerosis; improving hyperlipemia, diabetes, hypertension, cerebral functions and hepatic functions; antioxidation; antistress; strengthening immune responses; improving antithrombotic effect; protecting cerebral neurons; anticancer effects, etc. Recently, it was reported that red ginseng contains a little amount of Rg3, a ginsenoside having various effects such as relaxation of blood vessels [J. Nat. Prod. 63, 1702(2000)], inhibition of platelet aggregations [Biol. Pharm. Bull. 21, 79(1998), Korean J. Ginseng Sci. 21, 132(1997)], protection of cerebral neurons [J. Neuroscience Res. 53, 426(1998), Neuro Report 9, 226(1998)], while ginsenosides Rg3, Rg5, Rh2, and Rh1 have anticancer activities [Jpn. J. cancer Res. 87, 357(1996), J. cancer Res. Clin. Oncol. 120, 24(1993), Anticancer Res. 17, 1067(1997), Cancer Letters 150, 41(2000), Dietary Anticarcinogenesis and Antimutagenesis 274(2000)]. Fresh ginseng has been customarily processed into white ginseng or red ginseng for long-term storage purpose. It has been also reported that red ginseng, contains trace amount of ginsenosides such as Rg3, Rg5, Rh1, Rh2, and Rh1 as well as maltol not contained in fresh ginseng or white ginseng, thus imparting improved therapeutic effects. There has been also invented an equipment which can prepare red ginseng extract from fresh ginseng or white ginseng (Korea Unexamined Patent Publication No. 10-2001-19628). Additionally, there have been also studies mainly focused on improving pharmaceutical effects by fortifying the aforementioned ginsenosides contained in small amounts in red ginseng. Recently it was revealed that ‘sun ginseng’, a type of ginseng processed via a novel method, wherein ginseng is heat-treated at a temperature of 120-180° C., a temperature much higher than that used in manufacturing red ginseng, thereby increasing the contents of the pharmaceutically important constituents usually contained in small amounts in conventional red ginseng and also producing new components, can improve existing pharmaceutical effects [J. Natural Products 63, 1702, 2000, Korea Patent No. 192678]. However, this method has a few drawbacks that it requires special equipments such as a high-pressure heater and it also requires a high heat treatment at a temperature higher than those used conventionally thus resulting in carbonization of ginseng, especially in the case of mass production. |
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, an object of the present invention is to provide a novel method for processing ginseng wherein the extract of processed ginseng can have remarkably fortified ginsenoside contents with much improved pharmaceutical effects. In the present invention, the inventors admixed ginseng and other pharmaceutically important herbal drugs and heated the mixture at a temperature of 70-120° C. and finally obtained the processed ginseng extract wherein the ratio of ginsenoside (Rg3+Rg5)/(Rb1+Rb2+Rc+Rd) is improved to 10-45, preferably 20-45, thereby drastically increasing the pharmaceutical effects of the processed ginseng extract. For example, thus obtained extract of the processed ginseng prepared according to the present invention has shown that the relaxation rate of blood vessels is increased about 65-97 times compared to those of conventional ginseng. Further, in the present invention, ginseng is mixed with at least one herbal drugs selected from the group consisting of Schizandrae Fructus, Crataegi Fructus, Corni Fructus, Chaenomelis Fructus, Mume Fructus, Citrus junos, Aurantii Fructus, apples, Fructus of Punica granatum and Citrus limon, and heat-treated at a temperature of 70-120° C., which results in conversion of protopanaxadiol-based saponins into ginsenosides such as Rg3, Rg5, Rk1 while protopanaxatriol-based saponins are converted into ginsenosides such as Rg2, F4, Rh1 and the like. Another object of the present invention is to provide extract of saponin fraction of the processed ginseng and extract of saponin fraction of the processed ginseng wherein the ratio of ginsenoside (Rg3+Rg5)/(Rb1+Rb2+Rc+Rd) is 10-45, preferably 20-45, with much improved pharmaceutical effects. Still another object of the present invention is to provide supplementary health drinks comprising concentrated or diluted extract of the processed ginseng aforementioned. Still another object of the present invention is to provide supplementary health foods or pharmaceutical drugs in the form of tablets, capsules, pills, granules, etc., comprising the extract of processed ginseng aforementioned. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.