Stable reverse water-in-fluorocarbon emulsions and water-in-fluorocarbon-in-water multiple emulsions comprising the reverse fluorocarbon emulsions. The reverse emulsions comprise a continuous phase which is a highly fluorinated or perfluorinated compound, a discontinuous aqueous phase and a fluorinated surfactant or mixture of surfactants. The multiple emulsions comprise an aqueous continuous phase and a discontinuous phase comprising globules formed of aqueous droplets dispersed into a highly fluorinated or perfluorinated compound. The emulsions can contain pharmacologically active agents, and are particularly suitable for pulmonary drug delivery.

Conventional direct emulsions consist of an oily phase dispersed in the form of droplets in a continuous aqueous phase. Direct fluorocarbon emulsions wherein the fluorocarbon is the oily phase have been used in various biomedical applications. Because of the high oxygen-carrying capacity of fluorocarbons, such fluorocarbon emulsions are particularly useful as blood substitutes to provide oxygen to the vascular system. After introduction of the emulsions, the oxygen dissolved in the dispersed fluorocarbon phase is released into the blood. Other medical uses include the treatment of cardiovascular and cerebrovascular diseases, coronary angioplasty, organ preservation and cancer therapy; diagnostic uses such as nuclear magnetic resonance and ultrasound; and veterinary therapy (Riess J. G., Blood Compatible Materials and Devices": Perspective Towards the 21st Century, Technomics Publishing Co., Lancaster, Pa., Ch. 14, 1991; Riess, J. G., Vox. Sang., 61:225, 1991). Conventional direct fluorocarbon emulsions have been described in, for example, EP-A-0 255 443, FR-A- 2 665 705, FR-A- 2 677 360, FR-A- 2 694 559, FR-A- 2 679 150, WO-A-93 01798, WO90/15807, EP-A-311473 and US 3,975,512.
The pulmonary administration of drugs constitutes a difficult problem because the introduction of drugs directly into the lungs cannot be effectively achieved by means of an aqueous solution. Fluorocarbon direct emulsions wherein the continuous phase is water are unsuitable for pulmonary drug delivery for the same reason.
The use of fluorocarbon liquids for pulmonary ventilation and drug administration via the pulmonary route has been described by Shaffer et al. (Art. Blood Subs. and Cells Immob. Biotech., 22:1994Pediatr. Pulmonol., 14:102, 1992) who contemplated the use of pure fluorocarbon liquids containing a dispersion of drugs in the form of solid powders. These compositions, however, result in non-homogenous, unreliable and irreproducible drug delivery due to the dispersion of the powdered agent in the fluorocarbon phase.
PCT Application No. WO91/18613 describes autoemulsifying "glasses" useful for the generation of reverse or multiple emulsions by contacting the "glass" with an appropriate aqueous phase. This document describes neither fluorinated nor non-fluorinated surfactants. Stable reverse fluorocarbon emulsions capable of effective intrapulmonary drug delivery are not disclosed.
EP-A-0-250 766 describes perfluoropolyether microemulsions of the water-in-oil type to be used as lubricants; these microemulsions contain low amounts of fluorocarbon (ca. 13-30% v/v).
Japanese Patent 57/109714 describes delivery of an anticancer agent to a desired site by mixing the agent with a magnetic fluid and applying a magnetic field to the resulting mixture. These fluids may be in the form of direct emulsions, reverse emulsions or multiple emulsions for intravascular administration. Again, this document does not describe stable reverse emulsions suitable for intrapulmonary drug delivery.
Thus, there is a need for stable fluorocarbon emulsions capable of homogeneous, reproducible pulmonary drug delivery in a controlled manner. The present invention satisfies this need.
The same preparations with a fluorocarbon as the continuous phase can be further utilized to deliver drugs and other materials to other body cavities including the gastrointestinal tract, peritoneal cavity, pleural cavity, subarachnoid ventricular spaces, etc.

Stable reverse and multiple fluorocarbon emulsions


A hose clamp identification marker for selectively identifying contents of a flexible hose. The hose clamp identification marker may be implemented in connection with a hose clamp and may comprise an open channel configured to straddle a hose. In this manner, the hose clamp identification marker of the present invention may be introduced to and removed from the hose clamp without disrupting continuity of treatment or requiring disassembly of the connection between the hose and a delivery device, such as a hollow needle.

Flexible hoses are well known and widely used in a variety of industries, including health, general industrial, semiconductor, food and beverage, transportation and specialty products, laboratory and pharmaceutics. The health and medical industries, in particular, rely heavily on flexible hoses and their associated hose clamps for various applications, such as enteral feeding, cardiopulmonary bypass, urinary and cardiovascular catheterization, intravenous drug and fluid administration, and the like.
Indeed, the delivery of medicines and fluids to a patient is one of the most important uses of flexible hoses and their associated clamps. Such delivery typically requires an intravenous feed line to communicate therapeutic liquid from a fluid reservoir (such as bottle or bag) to a hollow needle via a flexible hose. The hollow needle is then inserted into a part of the patient's body (i.e., vein) for delivery of the therapeutic liquid to the patient.
Hose clamps are typically used with flexible hoses to allow the hose to be partially or completely compressed and control (or terminate) the flow of the fluid in the hose. The hose clamp can also be used to facilitate removal or insertion of an intravenous feed line. Such hose clamps and their uses are known in the art. See, for example, U.S. Pat. No. 5,203,056, the disclosure of which is incorporated herein by reference.
Identifying markers are also typically known and used in the art. Identifying markers are capable of identifying a drug or other fluid treatment administered through a hose. See, for example, U.S. Pat. No. 5,316,246, the disclosure of which is incorporated herein by reference. Existing identifying markers, however, are seldom used in connection with a hose clamp as it is often desirable to change the treatment or a specific characteristic of the treatment, such as priming volume, without changing or disconnecting the hose through which it is administered. As existing identification markers require that the hose be threaded through the marker to properly retain the marker in position, it is virtually impossible to independently remove or replace the marker without disrupting continuity of treatment.
Other problems are also present with existing identification markers. First, existing markers only loosely fit to the hose clamp, which may result in undesired marker movement. Second, because current markers do not closely match the contours of the hose clamp, corners and edges of the marker may protrude from the clamp body. This is particularly problematic where the hose clamp is closely proximate the patient's skin. Indeed, movement of the marker may gouge or otherwise discomfort the patient. Any corners or edges protruding from the marker only aggravate this problem.


A liquid crystal display element is provided with a first insulating substrate having spacers and an alignment layer that covers the entire surfaces of the spacers, and a second insulating substrate having at least an alignment layer. The liquid crystal display element is arranged so that the first and second insulating substrates are bonded to each other by allowing the alignment layer on the spacers of the first insulating substrate and the alignment layer on the second insulating substrate to soften and adhere to each other by applying a pressure under heat, and liquid crystal is injected into the gap in between.

Conventionally, liquid crystal display elements, which are made by bonding paired substrates to each other with their electrode-bearing surfaces facing inside and by sealing liquid crystal into the gap between them, have been well known. In such liquid crystal displays, when the distance between the opposing substrates varies due to deformation of the substrates caused by external pressure or other adverse effects, changes in the threshold-voltage value, short circuit in the electrodes between the opposing substrates, disturbance in the orientation of the liquid crystal molecules, etc. tend to occur, thereby making it impossible to provide good display images. For this reason, in order to keep the distance between the paired substrates constant, some methods for placing spacers between the substrates have been suggested; conventionally, either of the following two methods is commonly adopted: (1) a method for spraying spherical particles and (2) a method for forming pillars made of an organic or inorganic material.
Specific examples of the method (1) include a dry method in which spherical fine particles, made of, for example, an organic resin, such as a polymer of divinylbenzenes, are dispersed in a gas flow of nitrogen and then sprayed on the substrates, and a method in which the spherical fine particles are mixed in an alcohol solution or other solutions and sprayed on the substrates in a mist state.
However, method (1) has the following problems: The first problem is that since the fine particles have a coagulating property whereby they coagulate with one another, it is difficult to spray them on the substrates in a uniform manner and consequently to achieve a uniform cell thickness. The second problem is that since it is difficult to control the adherence location of the fine particles, the particles, which have been unintentionally sprayed on pixels, tend to cause defects in the orientation, resulting in low display quality. Further, the third problem is that since the substrates are supported by the spherical fine particles that function as spacers only at their contact points, it is difficult to obtain sufficient strength against external pressure.
Moreover, method (2) more specifically refers to a method in which: an organic or inorganic film is formed with a desired thickness, a resist film is formed thereon, and the resist film is irradiated by ultraviolet lights using a photomask, thereby forming pillars that function as spacers. Here, instead of the resist film, for example, photosensitive organic resins, such as photosensitive polyimide or photosensitive acryl resins, can be adopted.
As described above, advantages of method (2) are that the pillars can be selectively formed on the outside of the pixels, and that the contact surfaces between the substrates and the pillars can be shaped into a desired pattern. Thus, method (2) is superior in the uniformity of the cell thickness, the strength against external pressure, and display quality, as compared with method (1).
Recently, ferroelectric liquid crystal has been taken notice of as a prospective liquid crystal material since it has superior properties, such as having spontaneous polarization and providing high-speed response. However, the disadvantage of ferroelectric liquid crystal is that since it has a structure whose molecule-regularity is closer to that of a crystal, once the molecular orientation has been disturbed, it is difficult to return to its original state, that is, it is susceptible to shock. For this reason, in order to solve the above-mentioned inherent problem with ferroelectric liquid crystal, it is essential to provide a substrate construction that is superior in shock resistance. In order to provide a method for manufacturing such a liquid crystal display element, method (2) is considered to be a more prospective candidate than method (1).
In general, in the conventional manufacturing method (2), after an alignment layer has been formed on an insulating substrate, spacers are formed on the alignment layer. However, the conventional manufacturing methods have the following various problems.
First, the manufacturing process of the spacers may give adverse effects, such as contamination, deterioration, and damage, on the alignment layer. Conventionally, in general, spacers are formed on a substrate that has been subjected to an alignment process, by using a photolithography process wherein photosensitive polyimide, photoresist and other materials are used. Here, solvents, which are used in the photolithography process, tend to give adverse effects on the alignment layer. In this case, since the alignment capability of the alignment layer is lowered, the orientation of liquid crystal molecules becomes ununiform, thereby causing degradation in the display quality.
Moreover, when consideration is given so that spacer materials do not affect the alignment layer, limitations, such as a limitation that spacer materials having a setting temperature higher than the alignment layer can not be used, have to be imposed on the spacer materials.
Furthermore, in the above-mentioned conventional manufacturing method, when the substrates are bonded to each other, the spacers that have been formed on one of the substrates and the alignment layer that has been formed on the opposing substrate are bonded to each other. Here, such a bonding process between the materials of different types raises the following problems: The bonding process is carried out while both of the spacers and the alignment layer are being softened by applying heat under pressure; therefore, when there is a great difference between the respective softening temperatures of the spacers and the alignment layer, the material having the lower softening temperature may not retain its shape upon having a temperature rise to the higher softening temperature. Consequently, for example, if the spacers are deformed, those spacers may enter the pixel portions, thereby causing problems, such as degradation in the display quality and low precision in the cell-thickness control. In contrast, if a sufficient temperature rise is not provided, a sufficient adhesive strength may not be obtained, thereby making the substrates susceptible to deformation under external pressure.

Liquid crystal display element with a portion of an alignment layer covers spacer is directly bonded to the alignment layer on the other substrate

The Secretary of State for Defence in Her Britannic Majesty's Government of the United Kingdom of Great Britain and Northern Ireland


A probe for measuring the thickness of frost accretion on a surface includes a plurality of measuring stages that are stacked substantially orthogonally to the base of the probe. Each measuring stage has an emitter that emits a light beam that is substantially parallel to the base and a receiver that receives the light beam after reflection on the frost.

It is known that, under particular meteorological conditions, accretions of frost may form on the aerodynamic surfaces of an aircraft in flight, thereby, on the one hand, modifying the aerodynamic profile and hence the aerodynamic characteristics of said surfaces and, on the other hand, making said aircraft heavier and modifying the trim thereof. Such accretions of frost may therefore render the aircraft uncontrollable and cause it to drop.
In order to study the meteorological conditions of frost formation and, thus, anticipate accretions of frost on the aerodynamic surfaces of an aircraft and avoid their consequences, specific campaigns of flight trials are conducted. These trials are aimed at improving the knowledge regarding the shapes of the natural accretions of frost that are apt to be laid down so as to validate already existing models, within the framework of the aircraft certification procedure. Thus, they make it possible to define the shapes of the accretions, to measure the thicknesses and spread thereof in particular about the profile of the aerodynamic surfaces and to determine the state of said profile.
As regards solely the measurement of the thickness of frost accretions, numerous probes are already known which operate by implementing physical principles such as electrical induction and propagation of ultrasounds, microwaves and light beams in frost.
For example, document U.S. Pat. No. 6,425,286 describes an electro-optical probe for detecting frost. This probe comprises a base for fixing it to a surface of the aircraft in contact with the aerodynamic flow, as well as an oblong casing, orthogonal to said base and provided with a cavity in which frost can accumulate. A light beam passes through the cavity and a sensor makes it possible to detect or not the presence of said beam. In case of frost, the latter obstructs the cavity so that the light beam may not be detected by the sensor. This probe furthermore comprises a heating device for melting the frost accumulated in the cavity. By counting the number of heating cycles, the probe can evaluate the total quantity of frost formed.
Regardless of the physical principle on which the operation of these known probes is based, experience shows that they can measure only limited thicknesses of frost and, sometimes, with low accuracy.

Probe for measuring the thickness of frost accretion on a surface


A polycrystalline Si thin film and a single crystal Si thin film are formed on an SiO2 film deposited on an insulating substrate. A polycrystalline Si layer is grown by thermally crystallizing an amorphous Si thin film so as to form the polycrystalline Si thin film. A single crystal Si substrate, having (a) an SiO2 film thereon and (b) a hydrogen ion implantation portion therein, is bonded to an area of the polycrystalline Si thin film that has been subjected to etching removal, and is subjected to a heating process. Then, the single crystal Si substrate is divided at the hydrogen ion implantation portion in an exfoliating manner, so as to form the single crystal Si thin film. As a result, it is possible to provide a large-size semiconductor device, having the single crystal Si thin film, whose property is stable, at a low cost.

Conventionally, so-called active matrix driving has been employed, and the active matrix driving is such that: thin film transistors (hereinbelow referred to as TFT) such as a-Si (amorphous Si) and p-Si (polycrystalline Si) are formed on a glass substrate, so as to drive a liquid crystal display panel, an organic EL panel, and the like. Further, by using the p-Si whose mobility is so high as to operate at a high speed, peripheral drivers have been integrated. Alternately, study has been performed with respect to forming of a device which utilizes higher-performance Si so as to integrate a system constituted of an image processor, a timing controller, and the like, that are required to have higher performance.
This is because the polycrystalline Si brings about the following problems: because of (a) a localized state in the band gap that is caused by incomplete crystallization, (b) deficiency in the vicinity of a crystal grain boundary, drop in the mobility that is caused by the presence of the localized state in the band gap, and (d) increase in an S coefficient (sub-threshold coefficient), performance of the transistor is too insufficient to form a high-performance device of Si.
Then, in order to form a higher-performance device of Si, not only laser crystallization, but also the following techniques have been proposed: a technique for improving crystallization, for example, further advanced techniques such as SLS (Sequential Lateral Solidification) and the like (for example, a specification of U.S. Pat. No. 6,300,175 (Publication date: Oct. 9, 2001), CLC (CW Laser Lateral Crystallization)(for example, A. Hara et al., "Ultra-high Performance Poly-Si TFTs on a Glass by a Stable Scanning CW Laser Lateral Crystallization", 2001 International Workshop on Active Matrix Liquid Crystal Displays—TFT Technologies and Related Materials—(AM-LCD2001), Digest of Technical Papers, p.227–230, Jul. 11–13, 2001, Japan Society of Applied Physics). These techniques are to deposit an a-Si film on a glass substrate so as to control the crystallization in a preferable manner, or so as to realize single crystallization.
However, in these techniques using laser, a merely Si film is heated to a high temperature so as to perform crystal growth while keeping a temperature of an insulating substrate whose heat resistance is low like glass etc. Thus, generally, a tensile stress of approximately 109Pa is exerted on the Si film, so that there occur such problems: cracks appear in the film, reproducibility in the TFT property is deteriorated, non-uniformity is large, and the like.
While, there is a technique in which the single crystal Si is bonded to the insulating substrate so as to make the film thinner (for example, Japanese Laid-Open Patent Application No. 211128/1993 (Tokukaihei 5-211128)(Publication date: Aug. 20, 1993). With this technique, it is possible to form an oxide film on the single crystal Si substrate, and to form the single crystal Si thin film thereon. However, when the single crystal Si thin film is to be bonded to an insulating substrate other than the Si substrate, for example, a glass substrate or a quartz substrate, there occurs such problem that Si is stripped because of a thermal-expansion-coefficient difference between Si and the insulating substrate such as the quartz substrate.
In order to prevent the foregoing damage brought about in the thermal-bond-strength-improving process due to the thermal-expansion-coefficient difference between Si and the quartz substrate, there is proposed a method of changing composition of crystallized glass (for example, Japanese Laid-Open Patent Application No. 163363/1999 (Tokukaihei 11-163363) (Publication date: Jun. 18, 1999).
Further, as described above, conventionally, there have been brought about dramatic improvements in (a) an integrated circuit element technique such that: the single crystal silicon substrate is processed and hundreds of millions of transistors are formed on the substrate, and (b) a thin film transistor (TFT) liquid crystal display technique such that: after a polycrystal semiconductor thin film such as a silicon film is formed on an amorphous material such as a glass substrate, they are processed into a transistor, so as to make picture elements and drivers of a liquid crystal display, as well as popularization of computers and personal information terminals using liquid crystal displays.
In these techniques, the integrated circuit element is made by processing a commercial single crystal silicon wafer whose thickness is scant 1 mm and diameter ranges from 150 mm to 300 mm, and forming a large number of transistors on the processed single crystal silicon wafer. Further, in the TFT liquid crystal display, an amorphous silicon film on an amorphous nonalkali glass is fused/polycrystallized by heat of laser etc., and the amorphous silicon film is processed, so as to form a MOS type transistor which functions as a switching element.
In fields of the liquid crystal display and the organic EL display using the TFT, a TFT of an amorphous silicon film or a polysilicon film is formed on a transparent glass substrate, so as to form a device of silicon for driving the picture element, that is, for performing so-called active matrix driving. Further, in order to integrate the peripheral drivers, the timing controller, and the like as a system in terms of the active matrix driving, forming of a higher-performance device of silicon has been studied. This is because the polycrystalline Silicon film brings about the following problem: because of (a) a localized state in the band gap that is caused by incomplete crystal, (b) drop in the mobility, or (c) increase in a sub-threshold coefficient (S coefficient) that are brought about by the presence of the localized state in the band gap in the vicinity of a crystal grain boundary, performance of the transistor is too insufficient to form a high-performance device of silicon.
Then, attention is paid to an SOI technique. The SOI is the abbreviation of Silicon on Insulator, and is a technique for forming a single crystal semiconductor thin film on an insulating substrate (this technique is seldom used to form a polycrystalline Silicon film). The technique has been actively studied since around 1981. Further, the SOI substrate used in the field of the integrated circuit is to dramatically improve performance of the semiconductor element by using preferable transistors. Thus, as long as the substrate functions as an insulating film, it does not matter whether the substrate is transparent or not, or it does not matter whether the substrate is crystalline or amorphous. In this field, when the transistor is formed by using the SOI substrate, elements are completely separated, so that there is little restriction in operating, thereby obtaining preferable property as a transistor.
Now, as a representative of the SOI substrate, a SIMOX (Separation by Implantation of Oxygen) substrate is on sale. In the SOI substrate, oxygen is implanted into a silicon wafer, and the thus formed silicon oxide layer separates a single crystal silicon thin film from a bulk of the substrate. Thus, oxygen which is an element much heavier than hydrogen is implanted to a predetermined depth so that the implantation is performed at high energy and at high dose. Thus, crystals are severely damaged, so that there occur the following problems: it is impossible to obtain sufficient property of the single crystal, or it is impossible to obtain complete insulating property because of deviation from stoichiometry of a silicon dioxide film portion.
Then, Tokukaihei 5-211128 discloses a technique such that: the single crystal silicon is bonded to the substrate, and this is made to be a thin film. This prior art is called "smart cut process", and is such that: hydrogen ions are implanted into a single crystal silicon substrate in accordance with an ion implantation process, and the resultant is bonded to an enforcing member, and minute bubbles are brought about in a hydrogen ion implanted layer by a heating process, and the single crystal silicon substrate is divided at the hydrogen ion implanted layer, so as to form the single crystal silicon thin film, so that the SOI structure is realized. As a result, it is possible to manufacture a single crystal silicon transistor whose element property is high. From this view point, the technique is superior.
However, as to this prior art, Tokukaihei 5-211128 discloses merely that: the oxide film is formed on the single crystal silicon substrate, and the single crystal silicon thin film is formed thereon. The suitability for other substrates such as the glass substrate for display is not taken into consideration. Then, Tokukaihei 11-163363 mentions examples in which other substrates are compared in terms of the bonding suitability. In the prior art, it is recited that: crystallized glass is used to prevent the damages of the substrate in the heating process for improving the bond strength with respect to the substrate, and composition thereof is changed so as to correspond to the silicon piece in terms of the thermal expansion rate.
However, the crystallized glass typically contains alkali atoms, and has property contrary to a transistor whose property is stabilized. Further, in the foregoing techniques, the single crystal Si substrate is shaped in a wafer of 6, 8, and 12 inches in diameter, so that the insulating substrate which is to be bonded is limited to a substrate of 6, 8, and 12 inches. Thus, it is impossible to manufacture large size liquid crystal display panel and organic EL panel. In a case of a small size panel, the manufacturing cost becomes high, and it is difficult to use the technique in practice.
Moreover, in a case of using a quartz substrate, when the single crystal Si substrate is bonded to the insulating substrate, the bond strength drops because of the thermal expansion rate difference. Further, in a case where a stress is exerted on a bonded interface, the TFT property is deteriorated because of differences and non-uniformity in the stress exerted on the interface.
Further, in the prior art, it is considered that: when the single crystal silicon substrate is bonded, it is impossible to obtain the sufficient bond strength unless exposed in a high temperature. Thus, a temperature for performing the heating process is 800° C. to 1200° C. It is considered that a high-heat-resistant crystallized glass whose strain point is not less than 750° C. is suitable, so that there occurs the following problem: the technique cannot be applied to a high-strain-point nonalkali glass, typically used in a liquid crystal panel of the active matrix driving, whose strain point is not more than 700° C.

Semiconductor device and manufacturing method thereof, SOI substrate and display device using the same, and manufacturing method of the SOI substrate


The present invention is directed to a stable nitroglycerin containing pharmaceutical composition, preferably a tablet which is prepared by direct compression technology. The formulation closely replicates the properties of nitroglycerin molded sublingual tablets (e.g. adequate disintegration and sublingual absorption), while reducing the problems experienced with compressed tablets (e.g. friability and weight variations). The stable tablets are characterized by a decreased migration of nitroglycerin, decreased potency loss, excellent content uniformity when stored. The preferred combination of components are: nitroglycerin/lactose dilution, hydrous lactose, glyceril monostearate, fumed silica, pregelantinized starch and calcium stearate. The preferred process employs direct compression technology to yield composition showing adequate disintegration, bioavailability and improved stability.

The present invention is directed to a nitroglycerin containing pharmaceutical composition, preferably a direct compressed tablet, stabilized by the presence of glyceryl monostearate. The formulation closely replicates the properties of nitroglycerin molded sublingual tablets (e.g., adequate disintegration and sublingual absorption), while reducing the problems experienced with compressed tablets (e.g., friability and weight variations). The stable tablets are characterized by a decreased migration of nitroglycerin, decreased potency loss, excellent content uniformity when stored. The preferred combination of components are: nitroglycerin/lactose dilution, hydrous lactose, glyceryl monostearate, fumed silica, pregelatinized starch and calcium stearate. The preferred process employs direct compression technology to yield a stabilized composition showing adequate disintegration and bioavailability.
The stabilization of nitroglycerin in solid dosage forms has been a subject of scientific interest for more than twenty years. This interest can be attributed to the finding that nitroglycerin, which is a liquid at normal temperatures, easily migrates from tablets to other tablets and/or to the container and container components. Nitroglycerin will migrate to the cap-liner and to other tablets such as aspirin if the two products are stored together in the same container. Plastics have various affinities for nitroglycerin depending on their polarity; hence tablets have not been successfully marketed in unit dose containers. In fact, the USP states that nitroglycerin tablets must be stored in glass containers.
Various attempts have been made to improve the molded tablet formulation to assure better stability. However, as of now, significant improvements have not been made in marketed products. In 1973, Parke-Davis and Co. added polyethylene glycol 3350 to molded tablet formulations. While this additive reduced the migration and loss of nitroglycerin to some degree, the content uniformity range increased upon storage. Hence, after one or two years"" shelf life, there was a risk of not meeting USP limits.
About this time, a number of stabilizing agents were screened and some were found to decrease the volatility of nitroglycerin in tablets. Among these were microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), and xcex2-cyclodextrin (BCD). For instance, a compressed tablet was prepared using the combination of MCC and PVP and marketed by Warner Chilcott Laboratories as NitroPRN(copyright). The tablet was far superior to the current molded tablets with respect to nitroglycerin migration and volatility. However, the high amount of water insoluble excipient (MCC) was not desirable since the tablet gave a less acceptable feel and slower disintegration under the tongue.
Several patents on the stabilization of nitroglycerin in tablets have been granted. U.S. Pat. No. 4,091,091 assigned to Eli Lilly and Co., described the use of water soluble PVP to improve the stability of molded nitroglycerin tablets. In this application, PVP is added from a solution and molded tablets are made by the traditional method. Another patent, U.S. Pat. No. 4,059,686 assigned to Nippon Kayaku, indicates that xcex2 cyclodextrin is an effective stabilizing agent.
The manufacturing process for nitroglycerin sublingual tablets is typically the traditional molded tablet method. In this process, a wet mixture of nitroglycerin concentrate and other ingredients is made and, while moist, is pressed into cylindrical cavities. The wet tablets are pushed out using pins, which are accurately aligned to the cavities, and dried. The method produces a porous, fragile, rapidly dissolving tablet. However, a high degree of weight variation occurs and this attribute, coupled with inter-tablet migration of nitroglycerin, does not adequately preserve satisfactory content uniformity upon storage. The higher content variation which occurs after aging of the tablets, even when stored in tightly closed glass containers, is attributed to inter-tablet migration.
Moreover, this method has certain disadvantages; among them are the need to incorporate stabilizing agents like PVP, or the nitroglycerin itself, in alcohol and the subsequent removal of this solvent. It is preferable to employ nitroglycerin in a non-alcoholic solution for safety purposes. Also, wet granulations may require a binder which would retard and reduce the release (dissolution) of nitroglycerin from the tablet matrix. In addition, the extra handling and safety concerns with the processing of a wet granulation make the use of this technique less desirable.
The preferable method to prepare an improved stabilized nitroglycerin tablet appears to be the use of a direct compression technology. By this means the complexity and safety concerns with the wet granulation process is obviated. Although much is known about the problem of nitroglycerin instability, an improved dry compression formulation which closely matches the original sublingual tablet has not been produced. Such a tablet would preferably meet the USP requirements for nitroglycerin molded tablets, be comparable to the molded tablets in texture, size and weight, and effectively reduce the potency loss and inter-tablet migration of the drug.
The literature reports a number of stabilized compositions, but none have been prepared by direct compression technology to mimic the properties of a molded tablet. The technology and formulation techniques used to prepare an improved nitroglycerin tablet, particularly one made by compression, have not been developed. The lack of technical improvement relates to the complexity of the formulation with respect to selection of excipients and stabilizing agents which can be used to closely mimic the physical and chemical attributes of molded tablets and afford a significantly improved stability, and similar disintegration and bioavailability.
It is an object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that are not susceptible to intertablet migration of nitroglycerin.
It is also an object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that offer improved weight control (i.e., low weight variation).
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that achieve the same pharmacological activity as molded sublingual tablets.
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that provide a comparable mouthfeel to molded sublingual tablets.
It is yet another object of the invention to use a non-explosive nitroglycerin triturate to manufacture nitroglycerin sublingual tablets.
It is yet another object of the invention to provide a pharmaceutical composition with no overcharge of nitroglycerin to prolong the shelf life.
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets whose manufacture removes the complexity of wet granulation procedures and the safety concerns associated to solvent use.
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that are characterized by decreased nitroglycerin volatility and superior stability profiles.
It is yet another object of the invention to provide new and useful compressed nitroglycerin sublingual tablets that exceeds current USP requirements for assay and content uniformity.
The invention achieves these objects by employing a nitroglycerin compressed tablet dosage form which is more stable, exhibits less tablet to tablet weight and content uniformity variation and is less prone to powdering (low friability) than compositions prepared by molding techniques. It has now been discovered that pharmaceutical compositions, such as tablets, containing nitroglycerin comprised of: nitroglycerin, glyceryl monostearate, calcium stearate, silica, starch and lactose are stabilized against the migration of the active agent from tablet to tablet when such tablets are in contact with each other. The compositions are of the same taste and similar mouth feel as molded compositions which have been available heretofore. In addition, the nitroglycerin containing tablets exceed the USP specifications and are bioequivalent to molded tablets.
It has further been discovered that such pharmaceutical compositions can be prepared by a direct compression method. The use of direct compression technology provides compositions which can be readily produced in an inexpensive, facile, efficient, hazard free and environmentally safe manner. In the preferred embodiment of the invention, nitroglycerin, glyceryl monostearate, hydrous lactose, calcium stearate, pregelatinized starch and hydrophobic fumed silica are blended and then compressed to form the sublingual tablet.
Other benefits and advantages of the present invention will become readily apparent to those skilled in the art from the following detailed description of the invention and the appended claims.
As indicated above, the active agent of the present invention is nitroglycerin. The novel pharmaceutical compositions of this invention can contain from about 0.5 to about 2 weight % of nitroglycerin, said weight % based on the total composition weight. This permits a variety of dosage strengths to be manufactured.
Pure nitroglycerin has a vapor pressure of about 0.00026 mm at 20xc2x0 C. and is a violent explosive which must be handled with great care. Commercially available nitroglycerin is, therefore, diluted to a concentration of 10 weight %, prior to the undertaking of pharmaceutical compounding and processing. This concentration of nitroglycerin was previously considered as flammable, but new Department of Transportation regulations have reclassified nitroglycerin concentrations above 2% as explosive. For safety reasons, nitroglycerin is diluted to a concentration below 2 weight %.
In practice, it is desirable to have a nitroglycerin dilution at a range that is suitable to produce various strength tablets that are currently prescribed. One common dilution of a given percentage of nitroglycerin is readily compounded with additional excipients to produce the various strength tablets. While the strengths can be readily compounded using a 10% dilution, because of current regulations, compounding is performed, and exemplified herein, using a lower 1.95% dilution.
In the preferred embodiment, the diluent is comprised of the main ingredient, lactose. Lactose influences, to a great extent, the flow behavior, compressibility and the taste of the compositions. It has been discovered that the presence of greater than about 90%, preferably about 95 to about 98%, weight % of lactose, said weight % based on the diluent weight, is surprisingly advantageous. In terms of weight % based on total tablet weight, preferably about 85 to about 95, optimally about 88 to about 93, weight % of lactose is present.
There are many lactoses known to those skilled in the art that are included in the scope of the present invention. As an example which is not meant to limit the scope of the invention, there are a number of well known commercially available lactoses in the market such as anhydrous lactose and hydrated lactose formsxe2x80x94monohydrates (TABLETTOSE sold by Meggle Co. of Germany), hydrous lactose fine, hydrous lactose fast flow and hydrous lactose G-200. Different grades of hydrous or anhydrous lactose may be used that enable the preparation of tablets with good compressibility, low friability and quick disintegration as well as affording protection from flammability.
In alternate embodiments of the present invention, additional excipients are included in the diluent along with the lactose. One of these additional excipients is an anti-sticking agent.
During the investigation of additional excipients which can be introduced into the compositions of the present invention, it has been discovered that the presence of about 0.1 to about 1, optimally about 0.1 to about 0.5, preferably about 0.3 to about 0.5, weight % of silica (a silica preferably falling within the class of finely divided silica), said weight % based on the total tablet weight, is surprisingly advantageous. Use of the silica in conjunction with other specified ingredients such as the lactose helps the flow of the powder blend and prevents sticking of tablets to punches. Despite the hydrophobic nature of some silicas, the optimized level employed in the formulation does not affect tablet performance.
There are a number of silicas known to those skilled in the art, and the present invention is meant to broadly encompass all of these silicas. The silicas can be precipitated (SYLOID(copyright) sold by Davison Division, W. R. Grace Company) or fumed, amorphous, colloidal or crystalline and in an anhydrous or hydrous form. Fumed silica or silicon dioxide (SiO2) is a colorless, tasteless amorphous powder that is insoluble in water and acids. These colloidal silica particles are sintered together in chain-like formations that possess surface areas of 50 to 400 M2/g, depending upon the grade.
Hydrophobic fumed silicas are well known commercially available materials, e.g. AER-O-SIL(copyright) R-972 sold by Degussa, Inc. of Teterboro, N.J., CAB-O-SIL(copyright) N70-TS sold by Cabot Corp. of Tuscola, Ill., TULLANOX(copyright) 500 sold by Tulco, Inc., (all of which are preferred for use herein), of the general class of amorphous precipitated silicas but of the pyrogenic (fumed) type which provide, according to Kirk-Othmer""s Encyclopedia of Chemical Technology (Third Edition) Vol. 20 at pages 768 and 778-779, an ultimate particle size of 1-100 nm, and an aggregate particle size of 2-3 xcexcm. Hydrophobic silicas are discussed in Kirk-Othmer""s Encyclopedia of Chemical Technology (Third Edition) Vol. 7 at pages 440-441.
The compositions of the present invention also include the presence of starch. There are many different starches known to those of skill in the art and the present invention includes, but is not limited to those listed in Grant and Hackh""s Chemical Dictionary, Fifth Edition. A preferred starch of the present invention is pregelatinized starch. The starch is present in an amount from about 5 to about 15 weight %, preferably about 5 to about 10 weight %, based on the total tablet weight.
An important ingredient which is included in the compositions of the present invention is a stabilizer. As indicated above, nitroglycerin is a volatile compound that exhibits poor physical stability when formulated without a stabilizer. The presence of the stabilizer decreases the potency loss of nitroglycerin in tablets, and thus its addition is important. The preferred stabilizer of the present invention is glyceryl monostearate.
During the investigation of stabilizers which can be introduced into the compositions of the present invention, it has been discovered that the presence of about 0.05 to about 10, preferably about 1 to about 5, optimally about 1.5 to about 4 weight % of glyceryl monostearate, said weight % of glyceryl monostearate based on the total tablet weight, is surprisingly advantageous. Use of the glyceryl monostearate in the amounts specified above, in conjunction with other specified ingredients, leads to a compressed sublingual tablet possessing superior stability.
Glyceryl monostearate is a waxy material that decreases the disintegration time of nitroglycerin tablets. To overcome this adverse effect, the use of a disintegrant is preferably employed in the present invention. It is widely known to those of skill in the pharmaceutical development area what constitutes a disintegrant and the amounts to be employed in pharmaceutical compositions. Non-limiting examples of common disintegrants include one or more water dispersible cellulose derivatives such as microcrystalline cellulose, sodium croscarmellose, starch, and starch derivatives such as sodium carboxymethylstarch.
Initially, the diluted nitroglycerin is blended with a preblend of the stabilizer (i.e., glyceryl monostearate) and diluent (i.e., lactose). Then the anti-sticking agent (i.e., silica), more diluent and the disintegrant are added to the blend.
The conventional procedure for making compacts requires the addition of a lubricant to the mixture before compression. Compression is accomplished by subjection of the dry blend under pressures by moveable punches operating in a die wherein the blend is confined. The lubricants are necessary to allow the ready ejection of the formed compact and to prevent the binding of the punches in the die. Lubrication is required only at the tablet-die interface to prevent sticking of the newly formed compact to the die walls. However, existing practical approaches to tablet lubrication require homogeneous distribution of lubricant within the entire tablet formulation.
Although there are various tableting lubricants which are commercially available, it has been determined that the use of a hydrophobic lubricant is preferred. Even more preferred is a lubricant which is the alkali metal salt of a fatty acid. In the most preferred embodiment of the present invention it has been determined that calcium stearate is the lubricant of choice in the present invention (calcium stearate is a well known commercially available material, e.g. calcium stearate NF powder sold by Mallinckrodt of St. Louis, Mo.). During the investigation of other excipients which can be introduced into the compositions of the present invention, it has been discovered that the presence of about 0.1 to about 1, optimally about 0.1 to about 0.5, preferably about 0.3 to about 0.5 weight % of calcium stearate, said weight % of calcium stearate based on the total tablet weight, is surprisingly advantageous. Use of the calcium stearate in the amounts specified above, in conjunction with the other specified ingredients, leads to a decrease in tablet weight variation.
Another aspect of this invention relates to the process for preparing the novel stabilized nitroglycerin tablets having the compositions described hereinbefore. The process by which the stabilized nitroglycerin tablets are prepared comprises the steps of: (a) commingling nitroglycerin with lactose to produce a nitroglycerin dilution (current regulations require that the content of the active agent be about 2 percent); (b) adding and mixing the nitroglycerin dilution with an excipient or combination of excipients selected from the group described hereinbefore to produce a blend; (c) compressing the blend under a force of about 200 to about 800 kg; and (d) thereafter, recovering the blend as a compressed product having a hardness of about 1-4 kp.
One embodiment of the present invention provides for the preparation of the formulation by milling glyceryl monostearate along with a small portion of hydrous lactose. Similarly, hydrophobic fumed silica is milled along with a small portion of hydrous lactose. Diluted nitroglycerin is blended with the milled glyceryl monostearate/hydrous lactose mixture in a blender for 5 minutes. Most preferably, an intensifier-bar is turned during mixing. The milled hydrophobic fumed silica/hydrous lactose mixture an a disintegrant, such as pregelatinized starch are added and blended for about 5 minutes. A lubricant, such as calcium stearate, is then added.
Blending for the purposes of discovering the present invention has been accomplished through the use of a V-blender. It should be understood, however, that there are different blending techniques known by those skill in the art that may be used with similar results. Variations of all blending times discussed herein of xc2x150% are permitted to obtain blend uniformity.
Once the ingredients are thoroughly blended, the composition is preferably subjected to compression since it is preferred that the compositions of the present invention be tablets. Therefore, conventional tableting equipment and standard tableting procedures are applied to the blended mixture to prepare compacted sublingual nitroglycerin tablets having improved stability. Compression is accomplished by subjecting the blended mix to high pressures by moveable punches operating in a die wherein the tablet mix is confined.
In preparing a tablet, the thoroughly blended mixture is directly compressed into tablets on a tablet machine. While any tablet machine known to those skilled in the art may be used to compress the blended mixture into tablet, in a preferred embodiment, tablets are compressed on any rotary press with weight control at a force of about 200 to about 800 kg at an average speed of about 75 RPM (65-85 RPM). Most preferably, an instrumented tablet press is employed for better control of tablet weights.
In one embodiment, the tablets are packaged and/or stored for a period of time. Tablets can be packaged in glass amber vials (25-100 tablets per vial).
Physical Characteristics of Compressed Sublingual Compositions
It is a desirable characteristic of the compacted pharmaceutical tablets of the present invention to be bioequivalent to molded nitroglycerin tablets. In this invention, the bioavailability of the active ingredient is not impeded by the processing or the excipients added to make a stable compressed nitroglycerin sublingual tablet. The present invention is surprisingly advantageous by including excipients which are necessary to impart physical characteristics essential for manufacture with existing compaction equipment, but without having adverse effects on the availability of nitroglycerin.
The initial disintegration time of the compositions of the present invention is about 25 seconds. Preferably, the disintegration of the compositions of the present invention is on the order of about 10 to about 40 seconds. Most preferably, the disintegration of the compositions of the present invention is on the order of about 20 to about 30 seconds.
A free flowing granulation is crucial in quickly and evenly filling the die cavity during compression in a high speed press. Uneven or poor flow of granulation results in erratic filling of the die cavity and consequently, weight variation. Small differences in weight are magnified as large relative standard deviations for a tablet with an average weight as low as 35 mg. Because diluted nitroglycerin is a non-flowable, wet appearing mixture, it is a major contributor to flow problems in a powder blend. Without the aid of the excipients, the impedance to flow of granulation is expected to be seen at the highest strength (0.6 mg) where the greatest amount of nitroglycerin is incorporated into the blend.
The compressed nitroglycerin compositions of the present invention show less weight variation than previously known molded nitroglycerin compositions. The weight variations of the compositions of the present invention are less than about 3% RSD. Preferably, the weight variations of the compositions of the present invention are on the order of 1-2% RSD. Most preferably, the weight variations of the compositions of the present invention are about 1% RSD.
The compressed nitroglycerin compositions of the present invention also show better content uniformity than previously known molded nitroglycerin compositions. The content uniformity variations of the compositions of the present invention are less than about 4% RSD. Preferably, the content variations of the compositions of the present invention are on the order of about 1% RSD to about 3% RSD. Most preferably, the content variations of the compositions of the present invention are on the order of about 2% RSD.
In addition, the compressed nitroglycerin compositions of the present invention show significantly less friability than previously known molded nitroglycerin compositions, thus indicating improved structural integrity against external mechanical forces, e.g. during packaging, shipping, handling. The friability of the compositions of the present invention is less than about 1%. Preferably, the friability of the compositions of the present invention is less than about 0.5%.
Further, the compressed nitroglycerin compositions of the present invention show consistent thickness and hardness when compressed into tablets. The thickness of tablets compressed from the compositions of the present invention is about 0.07 to about 0.10xe2x80x3. The hardness of tablets compressed from the compositions of the present invention is greater than about 1 kp. Preferably, the hardness of tablets compressed from the compositions of the present invention is on the order of about 1-4 kp. The tablet hardness is sufficient to enable handling without risk of tablet breakage.
It will be apparent to those skilled in the art that the compressed sublingual tablets of the present invention may be multilayer tablets and have various shapes, colors, and sizes. Further, it will be apparent that these tablets once formed may be coded and/or coated by a variety of procedures well-known to those skilled in the art. Still further, the coated tablets may be subjected to a polishing procedure or other routine processes, which have been carried out on compressed tablets prior to this invention.
The term xe2x80x9ctabletxe2x80x9d as used herein includes tablets of any shape and includes caplets, which are tablets having a capsule shape. If desired, a pharmaceutically acceptable coloring agent may be added to the tablets. The compressed tablets may also be coated with a pharmaceutically acceptable polymer, gelatin, or sugar coating. The addition of coloring agent, polymer, gelatin, or sugar coating can be accomplished by anyone skilled in the art.
While various listed ingredients in the specification and claims have the suffix xe2x80x9cUSPxe2x80x9d (United States Pharmacopia) or xe2x80x9cNFxe2x80x9d (National Formulary), this is intended only to better identify the ingredient, or its purity, and not to limit the invention in any way to the use of ingredients so marked, since identical materials are available under other designations e.g. in foreign countries.
The present invention also comprises a product prepared by the methods of manufacturing the compressed nitroglycerin-containing compositions described above. The product is preferably a compressed nitroglycerin sublingual tablet prepared according to a process having the steps comprising: (a) blending ingredients selected from the group consisting of nitroglycerin, hydrous lactose, glyceryl monostearate, calcium stearate, starch and hydrophobic fumed silica; (b) compressing said blend under a pressure of 200 to about 800 kg; and (c) recovering said blend as a compressed product. In one embodiment, the process further comprises the step of diluting the nitroglycerin prior to blending the ingredients.
The preferred ingredients in the process are nitroglycerin, lactose monohydrate, calcium stearate, silica, starch and glyceryl monostearate in the following amounts: 0.5 to about 5 weight % of nitroglycerin; 88 to about 93 weight % of lactose; 0.3 to about 0.5 weight % of silica; 0.3 to about 0.5 weight % of calcium stearate; 5 to about 15 weight % of starch and about 0.5 to about 10 weight % of glyceryl monostearate. The products, preferably compressed into tablets, and made by the process have the following physical properties: disintegration on the order of about 20 to about 30 seconds; weight variations on the order of about 1 to about 2% RSD; content variations on the order of less than about 4% RSD; friability on the order of less than about 1%; thickness on the order of about 0.07xe2x80x3-0.10xe2x80x3, and hardness on the order of about 1-4 kp.

Compressed nitroglycerin tablet and its method of manufacture


An object of the invention is to provide a method of producing an optical waveguide comprising a siloxane-containing polymer film, capable of controlling a refractive index easily and finely, and an optoelectronic hybrid substrate using the optical waveguide, capable of controlling a refractive index easily and finely, and reducing the effect of the surface roughness of the substrate. In particular, it relates to a method of producing an optical waveguide comprising a siloxane-containing polymer film containing a metal obtained by the thermal polymerization of a siloxane-containing polymer film formation solution added with a metal alkoxide on a substrate, and an optoelectronic hybrid substrate comprising a combination of an optical waveguide produced as mentioned above, a photoelectric element and an electric circuit on a ceramic substrate.

1. Field of the Invention
The invention relates to a method for manufacturing an optical waveguide comprising an optoelectronic integrated circuit (OEIC), an optical waveguide, an LSI for OEIC control, an IC and a high frequency electric circuit on one substrate and an optoelectronic hybrid substrate using the optical waveguide, more specifically to a manufacturing method of an optical waveguide using a siloxane polymer, and an optoelectronic hybrid substrate using the optical waveguide comprising a siloxane polymer.
2. Description of the Prior Art
In response to demand for information processing of higher speed in optical communication systems or computers, use of light in signal transmission between integrated circuit chips, between substrates on which integrated circuit chips are mounted, or between boards comprising a plurality of integrated circuit substrates, is studied. However, since processing of transmitted signals is conducted in electronic parts in the case where light is used for signal transmission, signal conversion between a light signal and an electric signal is necessary in such an optical information processing.
In a conversion area of a light signal and an electric signal, a light transmission path comprising an optical fiber or an optical waveguide, or an photoelectron conversion element such as a laser diode and a photodiode is used. Therefore, in a circuit for optical information processing, an optoelectronic integrated circuit (OEIC) comprising a combination of the light transmission path or the photoelectron conversion element, a photoelectric element and an electronic circuit, an optical integrated circuit (optical IC) for processing information only with a light wave, an integrated circuit for controlling an electronic element or processing an electric signal, such as an IC or an LSI, and a high frequency electric circuit for driving an electronic part at a high speed coexist.
Hitherto, a module assembled with individual optical parts and electronic parts has been used as a photoelectron conversion element. Further, a light source system comprising a gas laser as a light source, and an optical system comprising a prism, a lens and a mirror was used. Recently, a comapct type optical system comprising a laser diode, a photodiode, an optical fiber and a rod lens has been used. And now research and development have been conducted strenuously for the practical use of an optoelectronic hybrid substrate, comprising an OEIC or an optical IC, an optical waveguide, an integrated circuit such as an LSI for OEIC control, and a high frequency electric circuit on one substrate.
According to the optoelectronic hybrid substrate, owing to high density integration, reduction of electric power, higher speed, higher reliability, improvement of mass productivity, easier assembly, and improvement of the stability after assembly can be achieved. However, in order for realizing an optoelectronic hybrid substrate, technology for forming an optical waveguide on a ceramic substrate, or a substrate comprising a thin film circuit laminated on a ceramic electric circuit substrate is necessary.
In the optical waveguide, precise control on a refractive index is necessary for a single mode light transmission. And for forming an optical waveguide, in particular, processing of a core portion and control of a refractive index of a core portion and a clad portion. For example, a typical specification for a silica-based single mode waveguide includes a core size of 7 .mu.m.times.7 .mu.m, the difference between a refractive index of the core portion and that of a clad portion of about 0.25%.
As a method of forming an optical waveguide, a method of preparing a core portion by forming an optical thin film of an appropriate thickness and applying a pattern processing thereto is generally used. As a method of forming an optical thin film, known methods include a CVD method, a FHD(Flame Hydrolysis Deposition) method, a vacuum evaporation method, a sputtering method, and an SOG (spin on glass) method. Among these examples, an SOG method is drawing attention since the method allows a thin film formation at a comparatively low temperature in a short time at a low cost.
In a sol-gel method using alkoxy silane as a starting material, which is an SOG method, a substantially complete inorganic silica can be obtained. However, it is difficult to obtain a film having a thickness of a several .mu.m or more in the method due to a large volume shrinkage at the time of depositing a film to generate a crack. Therefore the method has a problem of difficulty in the application in the production of a silica-based single mode optical waveguide where a thickness of at least 15 .mu.m is required for the core and clad portions. Further, there is another problem of a large internal stress of an obtained film, which causes a birefringence.
On the other hand, use of organic materials such as polyimide, PMMA (polymethyl methacrylate) and polycarbonate in addition to silica as a material of an optoelectronic hybrid substrate is advocated. Although knownforeasy film formation and a low cost, these organic materials have problems such as a high transmission loss and a high loss at a portion connecting with an optical fiber due to a refractive index larger than a silica-based material. Besides, these material excluding polyimide have problems such as high water absorption, a low decomposition temperature and a low glass transition point.
In the case polyimide fluoride is used as an optical waveguide material, there is a problem that a Fresnel reflection loss at the time of connecting with a silica-based optical fiber becomes larger due to a large difference between a refractive index of polyimide fluoride, which is about 1.53 and a refractive index of a silica, which is about 1.44. Besides, there is another problem of difficulty in connecting with a silica-based single mode optical fiber due to a multi mode light transmission.
Japanese Unexamined Patent Publication JP-A 5-66301(1993) discloses an optical waveguide material comprising siloxane-containing polymer and an optical material using thereof, which allows easier control on a refractive index in combination with another element substituting a silicon element. The disclosure suggests a method of changing a refractive index of an unsubstituted polymer by partially substituting a tetravalent element except silicon or a trivalent element except rare earth elements for a silicon element in a siloxane-containing polymer in a substitution method for obtaining an aimed siloxane polymer by hydrolysis and polymerization of a silane chloride and a chloride of an element to be substituted, such as A1.
The method has a problem of difficulty in reaction control since highly reactive materials are mixed. Therefore there is a problem that a sophisticated technology and an expensive equipment are necessary for producing a stable mixture with an optional mixing ratio.
The Japanese Unexamined Patent Publication JP-A 6-109936 (1994) and the U.S. Pat. No. 5,062,680 disclose an optical waveguide comprising a deuterated or halogenated siloxane polymer. The siloxane-containingpolymer allows easy processing and a low loss in the range of a visible light and an infrared light in producing an optical waveguide. However, the use of deuterium causes increase of the cost and the use of a halogen element, which is highly active, causes a problem in handling.
In general, various conditions are required for an optical waveguide, such as a smooth film surface of an optical waveguide with a surface roughness (Ra) of at least 1/10 or less of a light source wavelength to be used, which is preferable for achieving a low propagation loss in the formation of a core portion, optional setting of an internal refractive index in the production of an optical waveguide particularly in the production of a single mode optical waveguide, where a fine refractive index control is required, an excellent flatness after film formation regardless of the unevenness or surface roughness of a base substrate in the case where an optical waveguide is formed on a thin film circuit substrate, adherence with a base substrate, and a heat resistance in mounting an optical device such as a laser diode or a photodiode or an electronic device such as an LSI by soldering in the case of formation of an optoelectronic hybrid substrate. Therefore, in order to achieve an practical use of an optoelectronic hybrid substrate, an optical waveguide allowing easy control of a refractive index produced In an SOG method with a simple equipment, and a production method thereof have been called for.

Method for manufacturing optical waveguide using siloxane polymer, and optoelectronic hybrid substrate using the optical waveguide


Methods for detecting risks for and/or causes of metabolic syndrome or hyperferritinemia in accordance with several embodiments can include the step of measuring the level of heptadecanoic acid in a blood sample of a subject. The methods of several embodiments can further include the step of deeming the subject as having or being at risk of metabolic syndrome if the amount of heptadecanoic acid is below 0.4% of all fatty acids in the sera or plasma. The methods for treating metabolic syndrome or hyperferritinemia according to several embodiments can also include the step of administering a daily dose of heptadecanoic acid to a subject suffering from metabolic syndrome or hyperferritinemia for a period of time from three weeks to twenty-four weeks, wherein the minimum daily dose comprises about 3 mg per lb (or 6 mg per kg) of body weight.

There is a worldwide pandemic of diabetes in humans. In addition to diabetes, more than one in every three adults in the United States, an estimated 86 million people have metabolic syndrome, also called prediabetes. An estimated 440 million people in the world will possibly have diabetes by 2030, and there is a dire need to stem concurrent pandemics of metabolic syndrome, type 1 diabetes and type 2 diabetes.
In human subjects, high serum ferritin and iron overload have also been associated with metabolic syndrome, type 2 diabetes, and type 1 diabetes. While iron overload is most commonly associated with a mutation in the HFE gene resulting in C282Y substitutions, there is increasing recognition of high serum ferritin that is not associated with known genetic mutations. Ferritin is a measurement of total iron body stores. High ferritin in the blood (i.e. hyperferritinemia) and associated iron overload have been associated with metabolic syndrome (prediabetes), type 2 diabetes and type 1 diabetes in humans. Until now, serum ferritin has not been routinely tested in human subjects, but the few screening studies known in the prior art have demonstrated that a surprisingly high percent (28% and 12%) of healthy elderly men and women in the United States have hyperferritinemia. It is unknown precisely how high ferritin increases the risk of diabetes, but proposed mechanisms include direct injury to the liver and pancreas from excessive deposition or indirect injury from increased oxidative radicals.
Like human subjects, bottlenose dolphin (Tursiops truncatus) subjects can also be susceptible to metabolic syndrome, including high insulin, glucose, triglycerides, fatty liver disease, and iron overload. Iron overload in dolphins, involving excessive iron deposition primarily in the liver's Kupffer cells, can be progressive with age and can be associated with elevated insulin, lipids, and liver enzymes. This disease is associated with neither mutations in the HFE gene nor increases in studied acute phase proteins. Similar to humans, iron overload in dolphins is treated with phlebotomy, and repeated treatments are needed throughout life due to returning elevations of serum ferritin. The underlying causes of iron overload and hyperferritinemia in dolphins are unknown.
Dolphins at the Navy Marine Mammal Program (MMP) are a well-studied dolphin population with regard to metabolic syndrome, and this population has a higher risk of developing metabolic syndrome when compared to wild dolphins, such as wild dolphins living in Sarasota Bay, Fla., for example. When comparing the two populations, neither body mass indices nor stress indices (i.e. cortisol) are risk factors for metabolic syndrome in MMP dolphins. In studies comparing values of blood-based indicators of metabolic syndrome, MMP dolphins have been older than Sarasota Bay dolphins; older age of the MMP dolphin population is further supported by its higher annual survival rates and longer lives compared to wild dolphins, including those living in Sarasota Bay. Proposed risk factors for metabolic syndrome in dolphins can include advanced age, differences in feeding and activity schedules, and differences in dietary fish. It can be hypothesized that differences in dietary fish (and certain fatty acids associated with particular types of fish) can be responsible for differences in the risk of metabolic syndrome and iron overload in dolphins.
In view of the above, it is an object of the present invention to provide a method for detecting protective and risk factors against and for metabolic syndrome and hyperferritinemia in mammal subjects such as dolphins and humans. Another object of the present invention is to provide a method for treating metabolic syndrome and/or hyperferritinemia in mammal subjects, such as dolphins and humans. Still another object of the present invention is to provide a method for detecting metabolic syndrome and/or hyperferritinemia in mammal subjects, such as for dolphins and humans that increases the level of heptadecanoic acid of the subject sera. Yet another object of the present invention is to provide a method for detecting and treating hyperferritinemia without resorting to phlebotomy. Another object of the present invention is to provide a method for detecting and treating metabolic syndrome and/or hyperferritinemia in mammal subjects, such as dolphins and humans that is easy to accomplish in a cost-effective manner.

This patent is subject to a terminal disclaimer.

Use of heptadecanoic acid (C17:0) to detect risk of and treat hyperferritinemia and metabolic syndrome

The United States of America, as Represented by the Secretary of the Navy


An organic light emitting display includes a display panel including pixels, a degradation sensing circuit which senses a threshold voltage of organic light emitting diodes included in the pixels and calculates an average degradation value defined by an average luminance value due to the degradation based on the sensed threshold voltage, a compensation target adjustor which adjusts a compensation target based on the average degradation value, each time the average degradation value is reduced by a previously determined reference value, and a data modulator which adds and subtracts a luminance compensation value determined depending on the adjusted compensation target to and from digital video data and modulates the digital video data.

1. Field of the Invention
Embodiments of the invention relate to an organic light emitting display, and more particularly to an organic light emitting display and a degradation compensation method thereof capable of compensating for degradation of an organic light emitting diode.
2. Discussion of the Related Art
An organic light emitting display, which has been considered as the next generation display, includes a self-emitting element capable of emitting light by itself, and thus has advantages including a fast response time, a high light emitting efficiency, a high luminance, a wide viewing angle, etc.
The organic light emitting display includes an organic light emitting diode (hereinafter, abbreviated to "OLED") serving as the self-emitting element. The OLED includes an anode electrode, a cathode electrode, and an organic compound layer formed between the anode electrode and the cathode electrode. The organic compound layer includes a hole injection layer, a hole transport layer, a light emitting layer, an electron transport layer, and an electron injection layer. When a driving voltage is applied to the anode electrode and the cathode electrode, holes passing through the hole transport layer and electrons passing through the electron transport layer move to the light emitting layer to form excitons. As a result, the light emitting layer generates visible light.
In the organic light emitting display, pixels each including the OLED are arranged in a matrix form, and brightness of the pixels is controlled based on a gray level of video data. The organic light emitting display is mainly classified into a passive matrix organic light emitting display and an active matrix organic light emitting display using thin film transistors (TFTs) as a switching element. The active matrix organic light emitting display selectively turns on the TFT serving as the active element to select the pixel and holds the light emission of the pixel using a hold voltage of a storage capacitor.
There are several factors which reduce the luminance uniformity between the pixels in the organic light emitting display. A deviation between electrical characteristics of driving TFTs of the pixels, a deviation between cell driving voltages of the pixels, a degradation deviation between the OLEDs of the pixels, etc. have been known as the factors. The degradation deviation between the OLEDs of the pixels is generated because the pixels each have a different degradation speed based on the same usage time. The degradation deviation between the OLEDs leads to an image sticking phenomenon, thereby reducing image quality of the organic light emitting display.
To compensate for a luminance reduction resulting from the degradation of the OLED, a technology which applies a uniform programming current to the OLED to thereby sense a threshold voltage of the OLED and differently adjusts video data for the light emission of the OLED based on the sensed threshold voltage, has been known. As the degradation of the OLED deepens, the sensed threshold voltage increases and an output luminance is reduced. Therefore, a related art technology sets a compensation target for the luminance compensation and modulates the video data based on the sensed threshold voltage, thereby adjusting the output luminance in conformity with the compensation target.
However, as shown in FIG. 1, in the related art technology, the compensation target is set to an ideal luminance of an OLED, which is hardly used (i.e., has not yet been degraded), and the degraded pixels are compensated for their luminances based on the compensation target. Therefore, as usage time of the OLED passed, a luminance gap between the compensation target and a luminance to be compensated gradually increases. Hence, in the related art technology, as usage time of the OLED passed, power consumption required to compensate for the degradation of the OLED gradually increases. In FIG. 1, 'Best Pixel' indicates a pixel showing the ideal luminance, and 'Worst Pixel' indicates a pixel which is degraded and is subject to compensation as usage time of the OLED passed.
Furthermore, in the related art technology, because the compensation target is set to the ideal luminance, the luminance gap between the compensation target and the luminance subject to compensation gradually increases as usage time of the OLED passed. Hence, a compensation error increases. One factor generating the compensation error is an IR drop resulting from a resistance difference of a cell driving voltage supply line based on its location. As the compensation error increases, a luminance balance and a color balance of a display image of the organic light emitting display may not be kept.

Organic light emitting display and degradation compensation method thereof


The laminated structure includes a lightweight and shape-retaining foamed resin base member, an outer circumference frame integrally laminated on the reverse side of the foamed resin base member along the outer circumference of an article, and bridging ribs connecting between respective points on the outer circumference frame. Accordingly, the present invention provides a lightweight laminated structure with low cost by reducing the amount of the resin used, since the molded synthetic resin outer circumference frame and bridging ribs have small projection areas.

1. Field of the Invention
The present invention relates to a laminated structure and a method for manufacturing the laminated structure, which is favorably used for automobile interior parts such as a door trim, rear side trim and luggage trim and other interior parts of vehicles, as well as for building materials, wall materials and interior panel in buildings and houses.
2. Description of the Related Art
The construction of the interior parts of an automobile will be described using the door trim as an example with reference to FIGS. 19 and 20.
The door trim 1 is composed of an integrated laminate comprising a surface skin layer 3 having an excellent surface appearance on the surface of a shape-retaining resin core material 2 having rigidity enough for mounting on a chassis.
A polypropylene based resin mixed with talc is used for the resin core material 2. A synthetic resin sheet such as a polyvinyl chloride sheet is used for the surface skin 3 that has intrinsically no shape-retaining property, and elastomer sheets such as TPO (thermoplastic olefin) sheet has been frequently used for the surface skin in recent years considering the effect on the environment and availability for recycling.
A conventional method for molding the door trim 1 will be described hereinafter with reference to FIG. 21. The main parts of the die assembly 4 for molding the door trim 1 comprises an upper die 5 capable of ascending and descending with a predetermined stroke, a stationary lower die 6 paired with the upper die 5, and an injector 7 communicating with the lower die 6.
A cavity 5a for molding the final shape of the door trim 1 is formed in the upper die 5 by closing the upper and lower dies 5 and 6, and a core 6a is provided in the lower die 6. A hoist cylinder 5b is connected to the upper die 5 for ascending and descending movement of the upper die with a predetermined stroke, and a manifold 6b and gate 6c provided at the lower die 6 serve as passageways of a molten resin from the injector 7.
Guide posts 6d are provided at four corners of the lower die 6 for maintaining a proper position of the ascending and descending upper die 5, and guide bushes 5c corresponding to respective guide posts 6d are provided in the upper die 5.
Accordingly, the surface skin 3 is set in the die assembly while the upper and lower dies 5 and 6 are open, and a molten resin M is injected into a cavity between the die assembly from the injector 7 through the manifold 6b and gate 6c after closing the upper and lower dies 5 and 6 with each other, thereby the resin core material 2 is formed into a desired curved shape to integrally mold the surface skin 3 onto the resin core material 2.
While the molten resin M is fed on the molding surface of the core part 6a with the die assembly open in FIG. 21 for the convenience of descriptions, the molded resin M is actually injected into the cavity after closing the upper and lower molds 5 and 6 each other.
However, it has been pointed out in the conventional door trim 1 that the material cost becomes high due to a large projection area of the resin core material 2 with a large weight of the article.
The injection pressure for molding is forced to be high due to the large projection area of the resin core material 2. As a result, the die assembly become expensive since a die structure durable to the high injection pressure is required in addition to a long period of molding cycles for cooling and solidifying a large quantity of the molten resin.
Furthermore, the surface skin 3 becomes poor in sound absorbing ability since an air-impermeable synthetic resin sheet is used as a base, making it impossible to expect the sheet to have a sound absorbing property against the noises generated in the cabin.

Laminated structure and method for manufacturing the same


A hydroponic tower including a cavity defining a front tower surface and a rear inside surface, and further including a plant plug holder inserted within a cut-out defined in the front tower surface. The plant plug holder includes an edge member that encircles the cut-out, and a base member that supports a plant plug and extends rearward from the edge member and into the cavity of the tower. The plug holder further includes a rear shroud top member and a pair of side members that maintain the position of the plant plug within the plug holder such that the plant plug contacts the rear inside surface of the cavity when inserted into the plug holder.

Given the continued growth of the world's population, and given that the regions allocated for agricultural pursuits have decreased or simply become less favorable to such activities, the ability of conventional farms to feed the world's growing population has become increasingly taxed. Additionally, since population centers and agricultural centers are frequently not co-located, and due to the time and expense associated with shipping agricultural goods, in many regions of the world only the wealthy are able to obtain adequate supplies of non-processed food, i.e., raw fruits and vegetables. Furthermore, the fruits and vegetables that do reach population centers are likely to be of decreased nutritional content and flavor, both due to the distance that they have traveled and the fact that much of today's produce is bred for durability and fertility rather than flavor & nutrition. As a result, there has been a renewed interest in soilless growing techniques that do not require the use of pesticides, drastically reduce the use of water, and allow for growing varietals that are bred for nutrition and flavor instead of durability.
Hydroponics is a soilless growing technique in which plants are grown using a liquid solution of water and nutrients. The roots of the plants are typically maintained in a fibrous or granular material, often comprised of plastic, and fed via a wick, drip, nutrient film, or other nutrient delivery system. Hydroponic growing systems are often established within indoor facilities, thus allowing them to be located in or near population centers. This approach also provides exceptional climate control (i.e., temperature, humidity, air flow, CO2 concentration, light wavelength, intensity and duration, etc.) as well as improved pest and disease control, thus allowing an indoor hydroponic farm to succeed in a region in which the outside environment and/or the soil conditions are inhospitable to the use of conventional farming techniques. Furthermore, hydroponic and other soilless growing techniques can yield extremely high plant densities, especially in those instances in which either horizontal stacking systems or vertical growth towers are used.
While hydroponic farming techniques offer a number of advantages over conventional farming techniques, in order to achieve large-scale adoption of these techniques it is vital that the cost per plant be competitive with the costs associated with conventional farming techniques. Accordingly, the present invention provides a plant plug holder that achieves increased planting consistency and simplified tower maintenance while minimizing tower leakage.

Hydroponic tower compatible plant plug holder


A stretching device for a leisure chair includes a base. Stretching assemblies are symmetrically and pivotally connected to two sides of the base. The stretching assembly includes a seat plate mechanism. The front part of the seat plate mechanism is pivotally connected to a leg mechanism. The rear part of the seat plate mechanism is pivotally connected to a backrest mechanism. A drive mechanism is provided between the stretching assemblies. The drive mechanism includes a front drive rod and a rear drive rod. The front drive rod and the rear drive rod drive the stretching assemblies to unfold or fold by a reciprocating motion device. Two ends of the front drive rod are fixedly connected to the leg mechanism. Two ends of the rear drive rod are pivotally connected to a first drive member. The middle part of the first drive member is pivotally connected to a second drive member.

At present, many rocking chairs, recliners, sofas, and the like are equipped with an electromechanical stretching device, on which a backrest, a seat cushion and a leg rest are mounted. The electromechanical stretching device is typically a combination of various mechanical connectors, which realizes the switching between a sitting posture mode, a television (TV)-watching posture mode and a lying posture mode through a drive mechanism. However, the connections between the drive mechanism and the mechanical stretching assemblies lack guidance, as a result, the motions of the mechanical stretching assemblies on both sides are generally not synchronized, which affects user experience.


Establishing an electronic collaboration area includes receiving from an application a collaboration area request that identifies a collaboration area template structure, receiving one or more collaboration area parameters relating to the collaboration area template structure, and establishing a collaboration area having content that is a function of the collaboration area template structure and the received one or more collaboration area parameters, the collaboration area being accessible to a plurality of collaboration area participants.

The following description relates to a method and system for simplifying the creation of a computerized collaboration area or environment.
Many collaboration tools exist today to help computer users communicate with other users in other locations in an efficient manner. For example, e-mail applications allow people to communicate in an asynchronous manner, whereby one person can send a message and another person can later reply to the message. Chat applications allow similar communications to take place in real-time, or synchronously. Network meeting applications have also been developed to provide a virtual space in which to hold real-time, synchronous meetings. Such applications can offer live whiteboards on which meeting participants can provide input, presentations or other objects for participants to review and edit, and chat services for communications among the participants. The applications can also provide, or be integrated with, teleconferencing or video teleconferencing services.
More recently, collaboration environments known as virtual rooms have been developed to allow teams of workers to interact with each other, either synchronously or asynchronously. For example, two groups attempting to negotiate a contract may be provided with a virtual room in which to hold the discussions electronically. The room may initially be provided with a draft contract, and various team members may be given access to the room so that they may review, edit, annotate, and comment on the contract and on the comments and edits of others. Initially, this process may take place asynchronously, whereby each person visits the room at his or her convenience. As the contract comes closer to being finalized, synchronous sessions, or meetings, may be established, so that multiple members are viewing the room at one time, and are able to communicate with each other, such as by teleconference, video teleconference, or chat.

Establishing a collaboration environment


The present invention refers to a label comprising a pasting part for pasting said label to an object and comprising an electronic device preferably for a radio frequency identification (RFID). In order to improve such a label, it is suggested that the electronic device is pivotably connected to said pasting part.

The present invention relates to a label comprising at least one pasting part comprising an adhesive agent for pasting the label to an object and comprising a holding part for holding an electronic device, preferably for radio frequency identification (RFID) and to a method for applying such a label to an object, as well as an object with a label and a device for applying the label to an object.
Such labels are commonly known in the art. The electronic device is usually referred to as a RFID tag which comprises an antenna which is connected to an integrated circuit including a receiver and a transmitter. Due to the integrated circuit, these are also referred to as IC tags. Of course, the electronic device can comprise different components and is not necessarily limited to a specific RFID tag.
Labels comprising a RFID tag are used for example for tracing, recognising and identifying different objects such as beverages, blister packs, cartons, pallets, etc. Generally, a label comprising a RFID tag is usually referred to as a "smart" RFID label.
It should be noted that it is also known to use RFID tags as theft prevention on goods, in particular valuable goods such as clothing, bottles of whiskey, etc. However, these latter RFID tags are generally not connected to a memory provided for storing data related to the object, since the tag is generally only calibrated to a particular resonant frequency, provided to react and trigger an alarm signal when the object with the tag passes a gate where the resonant frequency is detected.
In recent years, there has been active development of RFID (radio frequency ID), which is a technique that uses wireless communications to perform reading and writing on IC chips.
The operating principle of this technique will be described with reference to FIG. 21.
In the RFID 5, an IC tag 4 (called an inlet or inlay) consisting of a thin film 3 containing an IC chip 1 and an antenna 2 is worked into a label, plastic card or suspended tag; this is used by being pasted to or suspended from the object that is being controlled.
A coil form antenna 2 is connected to the IC chip 1 that forms the essential part of the IC tag 4; when electromagnetic waves from a reader-writer 6 strike this antenna, a current is generated, and the IC chip 1 is driven using this current, so that data transmitted from the reader-writer 6 is received, and information stored in the memory of the IC chip 1 itself is transmitted by wireless transmission.
A memory is contained in the IC chip 1; this memory ordinarily includes a system region that cannot be rewritten, and a user data region that can be rewritten (some chips do not have a region that can be rewritten).
Since the information contained in the system region is invariable, this information cannot be falsified or copied, and is therefore superior in terms of security. Various frequencies are used in RFID, such as long wave at several hundred kilohertz, short wave at several tens of megahertz, UHF at several hundred megahertz, microwave at several gigahertz and the like. This also varies slightly according to the country involved. Characteristics such as communications distance, directionality, communications rate, noise, electromagnetic interference and the like vary according to the frequency used, so that it is necessary to select this frequency in accordance with the object of utilization and the surrounding environment.
Furthermore, though this also varies according to the frequency, electromagnetic waves are absorbed by metals and water especially in RFID in the UHF band; accordingly, if metals or water are present in the vicinity of the reader or IC tag, there may be instances in which information of the IC tag cannot be read or written.
In order to solve this problem, it is necessary to remove the offending object, or to utilize a special IC tag and frequency that are unaffected.
There are also other situations where the performance of the label is not sufficient. Depending on the composition or shape of the object on which the tag or label is affixed, the performance of the tag can be greatly impeded due to the nature of RFID and the laws of physics. In these cases, human intervention is generally required either for orienting the object or manually entering the data of the tag into a computer system, which would normally have been transmitted from the RFID tag. This human intervention increases the costs and chances of error, and slows down the whole identifying operation.
It is, therefore, an object of the present invention to provide an RFID tag carrying label, which enables an enhanced performance when data processing with the tag is requested, in particular reading or writing over greater distances. It is furthermore an object of the present invention to allow to attach the label to an object so that the label is separated from the object by a specific distance, thus preventing a shortening of the communication distance by absorption or reflection of electromagnetic waves due to the effects of the material of contents (metal, moisture or the like) of the container or the like that constitutes the object.


Disclosed is a plate-like belt buckle for storing a spare key for an automobile, comprising a groove diagonally formed in the rear side of said belt buckle for receiving said spare key; and a plurality of holding lugs for enclosing and holding said spare key received in said groove.

The present invention concerns a belt buckle for storing a spare key for an automobile.
Generally an automobile driver stores the spare key in a storing device attached to a portion of the outside of the body of an automobile. Hence, the spare key may be used by a thief to steal the automobile. Moreover, the structure of the conventional storing device is too complicated to simply store the spare key, thus decreasing the utility.

Belt buckle for storing a spare key for an automobile