This invention relates to stable non-aqueous formulations which are suspensions of proteinaceous substances or nucleic acids in non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity. More specifically, the present invention relates to stable protein or nucleic acid formulations wherein the compound remains in stable, dry powder form, yet the formulation is flowable and, therefore amenable to delivery to an animal via injection, transdermal administration, oral delivery or using an implantable device for sustained delivery. These stable formulations may be stored at elevated temperatures (e.g., 37xc2x0 C.) for long periods of time and are especially useful as flowable formulations which can be shipped and/or stored at high temperatures or in implantable delivery devices for long term delivery (e.g., 1-12 months or longer) of drug.

This invention relates to stable non-aqueous formulations of proteins and nucleic acids. The stable formulations of the present invention are suspensions of particles containing proteins or nucleic acids in non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity.
References:
The following references are referred to by numbers in brackets ([ ]) at the relevant portion of the specification.
1. Ahern and Manning, Eds., Stability of Protein Pharmaceuticals, A: Chemical and Physical Pathways of Protein Degradation, Plenum Press, New York, 1992.
2. Wang et al., 1988, J. Parenteral Science and Technology 42: S4-S26
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The disclosure of each of the above publications, patents or patent applications is hereby incorporated by reference in its entirety to the same extent as if the language of each individual publication, patent and patent application were specifically and individually incorporated by reference.
Peptides, polypeptides, proteins and other proteinaceous substances (e.g., viruses, antibodies), collectively referred to herein as proteins, have great utility as pharmaceuticals in the prevention, treatment and diagnosis of disease. Proteins are naturally active in aqueous environments, thus the preferred formulations of proteins have been in aqueous solutions. However, proteins are only marginally stable in aqueous solutions. Thus, protein pharmaceuticals often require refrigeration or have short shelf-lives under ambient conditions. Further, many proteins have only limited solubility in aqueous solutions. Even when they are soluble at high concentrations, they are prone to aggregation and precipitation.
Proteins can degrade via a number of chemical mechanisms, including deamidation of asparagine and glutamine; oxidation of methionine and, to a lesser degree, tryptophan, tyrosine and histidine; hydrolysis of peptide bonds; disulfide interchange; and racemization of chiral amino acid residues [1, 2 and 24-28]. Water is a reactant in nearly all of these degradation pathways. Further, water acts as a plasticizer which facilitates unfolding and irreversible aggregation of proteins. Since water is a participant in almost all protein degradation pathways, reduction of the aqueous protein solution to a dry powder provides an alternative formulation methodology to enhance the stability of protein pharmaceuticals. Proteins can be dried using various techniques, including freeze-drying, spray-drying and dessication. Aqueous solutions of proteins are thus dried and stored as dry powders until their use is required.
A serious drawback to drying of proteins is that often one would like to use proteins in some sort of liquid form. Parenteral injection and the use of drug delivery devices for sustained delivery of drug are two examples of applications where one would like to use proteins in a liquid form. For injection, dried proteins must be reconstituted, adding additional steps which are time-consuming and where contamination may occur, and exposing the protein to potentially destabilizing conditions [15].
The sustained parenteral delivery of drugs, in particular proteins and nucleic acids, provides many advantages. The use of implantable devices for sustained delivery of a wide variety of drugs or other beneficial agents is well known in the art. Typical devices are described, for example, in U.S. Pat. Nos. 5,034,229; 5,057,318; and 5,110,596. The disclosure of each of these patents is incorporated herein by reference.
Proteins are only marginally soluble in non-aqueous solvents, and such solvents typically unfold and denature proteins [4, 16]. Solubilization of native proteins in non-aqueous solvents typically requires derivatization or complexation of the protein [12]. In attempting to achieve enzymatic catalysis in organic media, Klibanov and others have shown that certain catalytic enzymes can be suspended in non-aqueous vehicles as powders, typically in hydrophilic organic solvents including alcohol ketones and esters [3, 5-11, 13 and 18-23]. With enzyme hydration levels xe2x89xa710% and/or the addition of low molecular weight protic compounds, these enzymes can have enough conformational mobility to exhibit appreciable enzymatic activity. Optimal activity levels are apparently achieved at enzyme hydration of approximately 30%. At a minimum, such enzymatic activity requires a level of xe2x80x9cessential waterxe2x80x9d hydrating the protein. However, hydration levels (generally 10-40% w/w water/protein) and/or protic solvents, such as those used in these studies, typically result in unacceptable stability of proteins for pharmaceutical purposes. A further requirement for catalysis in non-aqueous solvents is that the enzyme be dried from a solution having a pH near the optimal pH for the enzymatic activity. This pH limitation is detrimental to storage of protein pharmaceuticals, because most protein degradation mechanisms are pH dependent, and it is often the case that proteins are most stable when dried at pH values far from the value where they exhibit bioactivity [1]. Further, such catalytic enzyme systems are not amenable to the addition of protein stabilizers, particularly those that function by hydrogen bonding to the protein and reducing enzyme hydration (e.g., carbohydrates) [14].
The use of perfluorocarbons as components of drug delivery vehicles for certain ophthalmic compositions has been disclosed [29, 30]. Similarly, suspensions of growth hormone in triacetin or polyethylene glycol has been published [31].
The field of gene therapy or gene transfer is advancing both experimentally and clinically. Nucleic acids have been transferred into cells using viral vectors such as adenovirus, retrovirus, adeno-associated virus, vaccinia virus, and sindbis virus, among others. Non-viral methods have also been used, including calcium phosphate precipitation, DEAE dextran, injection of naked DNA, electroporation, cochleates, cationic lipid complexes, liposomes, polymers (such as dendrimers and PLGA), virosomes, and the like.
DNA complexed with cationic lipids and/or liposomes has been shown to be an efficient means of transfecting a variety of mammalian cells. Such complexes are simple to prepare and may be used with a wide variety of DNA""s and RNA""s with little restriction to the size of nucleic acid. They have the ability to transfect many different cell types with efficiency and are not immunogenic [32, 33, 35, 36]. Current nucleic acid formulations, including DNA/liposome and RNA/liposome complexes, must be mixed shortly before administration, resulting in inconvenience in manufacture, shipping, storage and administration [35, 37]. Frequently, these two-part formulations are not very highly concentrated, requiring the administration of large volumes of solution. Dry powder formulations containing lyophilized nucleic acid/liposome complexes have also been used [34, 41], but they require reconstitution with suitable aqueous solution just prior to administration. Aqueous complexes are inherently unstable and lose most, if not all, of their transfection activity within hours or a few days [41].
Consequently, there is a need for pharmaceutical compositions that can overcome these limitations of the prior art. Such a composition should maintain the stability of the active compound, preferably at both room and body temperature (25 and 37xc2x0 C.), and exist in at least a flowable state for injection, incorporation into delivery systems designed for immediate, delayed, or long term administration or other means of administration.
The present invention provides stable non-aqueous formulations which are suspensions of peptides, polypeptides, proteins and other proteinaceous substances (xe2x80x9cproteinsxe2x80x9d or xe2x80x9cproteinaceous substancesxe2x80x9d) or DNA- and RNA-containing compositions (xe2x80x9cnucleic acidsxe2x80x9d) in anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity. More specifically, the present invention relates to stable formulations wherein the proteinaceous substance or nucleic acid remains in stable, dry powder form, yet the formulation is flowable and, therefore amenable to delivery to an animal via, for example, injection, ambulatory infusion or an implantable device for sustained delivery. These stable formulations may be stored at elevated temperatures (e.g., 37xc2x0 C.) for long periods of time and are especially useful as flowable formulations which can be shipped and/or stored at high temperatures or in implantable delivery devices for long term delivery (e.g., 1-12 months or longer) of drug.
In one aspect, the invention provides stable protein compositions comprising a proteinaceous powder wherein the protein hydration in said powder is less than about 10%; and at least one anhydrous, aprotic, hydrophobic, non-polar, low-reactivity vehicle. In a preferred embodiment, up to about 30% (w/w) proteinaceous powder may be used in these flowable compositions.
In another aspect, the invention provides methods for preparing stable protein compositions, said methods comprising suspending a proteinaceous powder with protein hydration less than about 10% in at least one anhydrous, aprotic, hydrophobic, non-polar, low-reactivity vehicle.
In a further aspect, the invention provides methods for treating a subject suffering from or susceptible to a condition which may be alleviated or prevented by administration of a proteinaceous compound, said methods comprising administering to said subject an effective amount of a stable protein composition comprising a proteinaceous powder wherein the protein hydration in said powder is less than about 10%; and at least one anhydrous, non-polar, aprotic, hydrophobic, low-reactivity vehicle.
In yet a further aspect, the invention provides stable nucleic acid compositions comprising a nucleic acid-containing powder wherein the nucleic acid hydration in said powder is less than about 10%; and at least one anhydrous, non-polar, aprotic, hydrophobic, low-reactivity vehicle.
In yet still another aspect, the invention provides methods for preparing stable nucleic acid compositions, said methods comprising suspending a nucleic acid-containing powder with nucleic acid hydration less than about 10% in at least one anhydrous, non-polar, aprotic, hydrophobic, low-reactivity vehicle.
In yet still a further aspect, the invention provides methods for treating a subject suffering from or susceptible to a condition which may be alleviated or prevented by administration of a nucleic acid-containing compound, said methods comprising administering to said subject an effective amount of a stable nucleic acid composition comprising a nucleic acid-containing powder wherein the nucleic acid hydration in said powder is less than about 10%; and at least one anhydrous, non-polar, aprotic, hydrophobic, low-reactivity vehicle.
The present invention is drawn to the unexpected discovery that suspending dry protein- or nucleic acid-containing particles in anhydrous, aprotic, hydrophobic, non-polar vehicles of low reactivity results in stable flowable non-aqueous formulations. Previously known formulations of proteinaceous compounds, which are dilute buffered aqueous solutions containing excipients such as EDTA or polysorbate 80 which must be stored at low temperatures (4-25xc2x0 C.), or lyophilized powders or particles which must often be stored at low temperature and must then be reconstituted before administration, form degradation products using degradation pathways such as acid/base catalyzed hydrolysis, deamidation, racemization and oxidation. Similarly, previously known formulations of nucleic acids, even those prepared from lyophilized powders, are administered as dilute aqueous solutions which are not stable for long periods of time and which must be stored at low temperatures. In contrast, the presently claimed formulations stabilize proteins and nucleic acid compounds at elevated temperatures (e.g., 37xc2x0 C.) and at high concentrations (i.e., up to about 30%).
Standard peptide and protein formulations consist of dilute aqueous solutions. Drug stability is usually achieved by varying one or more of the following: pH, buffer type, ionic strength, excipients (EDTA, polysorbate 80, etc). For these formulations, degradation pathways requiring water (hydrolysis, deamidation, racemization) cannot be fully stabilized. In contrast, in the present invention, proteinaceous compounds formulated in non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low-reactivity, such as mineral oil (MO), perfluorodecalin (PFD), methoxyflurane (MF), perfluorotributylamine (PTA) and tetradecane (TD), were shown to be chemically and physically more stable than those formulated in aqueous solution. MO, PFD, MF, PTA and TD are considered anhydrous, aprotic, hydrophobic, non-polar vehicles of low reactivity. Such vehicles decrease the rate of degradation since they isolate the proteinaceous compounds from water and they lack the ability to contribute protons or other reactive moieties to degradation reactions.
The invention consists of using anhydrous, aprotic, non-polar, hydrophobic vehicles with low reactivity such as MO, PFD, MF, PTA or TD to stabilize protein formulations against both chemical and physical degradation. The discovery consists of the realization that use of MO, PFD, MF, PTA or TD improves the overall stability of proteins in a wide range of formulation conditions, including high concentrations and elevated temperatures, thus making possible shipping and/or storage of protein formulations at ambient temperature and the delivery of proteins in long term implantable devices that would not otherwise be feasible. The present invention provides flowable pharmaceutical formulations of proteinaceous substances that exhibit the requisite protein stability. These non-aqueous formulations comprise two components: 1) a protein in a stabilized powder formulation of low protein hydration; and 2) an anhydrous, hydrophobic, aprotic, non-polar vehicle of low reactivity and solubility power towards protein compounds. Optionally, the dry powder form of the protein may contain stabilizers and other excipients. Such stabilizers and excipients are those that further reduce protein hydration or protect from interfacial tension or other dehydration process-specific destabilization known to those skilled in the art.
Among other factors, it has been surprisingly discovered that when dispersed in certain vehicles, protein powders can display significantly greater stability than that observed for the dry powder alone. Such vehicles include long-chain alkanes, most preferably perfluorinated forms of alkanes. The present invention is especially advantageous because it provides the capacity to store proteins under ambient conditions for extended periods or to deliver proteins from implantable pumps for extended durations.
Lipid/DNA and lipid/RNA complexes facilitate nucleic acid uptake into cells both in vitro and in vivo. However, such complexes are inherently unstable in solution, losing most, if not all, of their activity after only a few days at ambient temperatures. This feature severely limits their applicability for use in such devices as implantable pumps, depot injection or other sustained release delivery systems where prolonged residence at 37xc2x0 C. is needed. Lyophilization of these complexes results in more stable compositions, but such powders require reconstitution prior to administration to render them flowable, and the reconstituted solutions are not stable. The present invention provides flowable pharmaceutical formulations of nucleic acids that exhibit the requisite stability. These non-aqueous formulations comprise two components: 1) a nucleic acid in a stabilized powder formulation of low hydration; and 2) an anhydrous, hydrophobic, aprotic, non-polar vehicle of low reactivity and solubility power towards nucleic acids. Optionally, the dry powder form of the nucleic acid may contain the nucleic acid in the form of lipid/DNA complexes, liposomes, ribozymes, viral vectors, virosomes, dendrimers, cationic polymers, PLGA particles or the like, and/or may optionally contain stabilizers and other excipients. Such stabilizers and excipients are those that further reduce hydration or protect from interfacial tension or other process-specific destabilization known to those skilled in the art.
The formulations of the present invention are useful in a variety of delivery systems, including, but not limited to, various pumping devices (syringes, infusion sets, syringe pumps, implantable pumps, etc.), transdermal reservoir systems, liquid fill capsules, injectable depot compositions and the like. An additional advantage of the present invention over the prior art is that the formulations of the present invention prevent back diffusion of water vapor (and subsequent hydrolytic degradation) because the hydrophobic vehicle of the formulation acts as a barrier to water vapor. This is especially important when the formulations are used in implantable devices which must remain in an aqueous environment at elevated temperatures for long periods of time.
A further advantage of the present invention is that it allows for the formulation of proteins or nucleic acids in a flowable state at extremely high concentrations (up to about 30% w/w). Because the protein or nucleic acid is in a dry state, it is not subject to the degradation processes (e.g., aggregation, precipitation or fragmentation) observed for high concentration aqueous solutions.
A. Definitions:
As used herein, the following terms have the following meanings:
The term xe2x80x9cchemical stabilityxe2x80x9d means that an acceptable percentage of degradation products produced by chemical pathways such as oxidation, hydrolysis or enzymatic action is formed and/or that acceptable biological activity is retained. In particular, a formulation is considered chemically stable if no more than about 40% breakdown products are formed and/or at least 40% biological activity is retained after one week at 37xc2x0 C.
The term xe2x80x9cphysical stabilityxe2x80x9d means that an acceptable percentage of aggregates (e.g., dimers, trimers and larger forms) and/or cleavage products is formed. In particular, a formulation is considered physically stable if no more that about 10% aggregates and/or clevage products are formed after one week at 37xc2x0 C.
The term xe2x80x9cstable formulationxe2x80x9d means that at least about 50% chemically and physically stable protein or nucleic acid compound remains after one week at 37xc2x0 C. Particularly preferred formulations are those which retain at least about 65%, and most particularly, at least about 80% chemically and physically stable compound under these conditions. Especially preferred stable formulations include those which remain flowable at high protein or nucleic acid loading (e.g., at or above 1%).
The terms xe2x80x9cproteinxe2x80x9d and/or xe2x80x9cproteinaceous compoundxe2x80x9d and/or xe2x80x9cproteinaceous substancexe2x80x9d mean peptides, polypeptides, proteins, viruses, antibodies, etc. which comprise polymers of amino acid residues bound together by amide (CONH) linkages. Both naturally-derived or purified and recombinantly produced moieties are included in these terms. These terms also include lipoproteins and post-translationally modified forms, e.g., glycosylated proteins. Analogs, derivatives, agonists, antagonists and pharmaceutically acceptable salts of any of these are included in these terms. The terms also include proteins and/or protein compounds and/or protein substances which have D-amino acids, modified, derivatized or non-naturally occurring amino acids in the D- or L-configuration and/or peptomimetic units as part of their structure.
The term xe2x80x9cexcipientxe2x80x9d means a more or less inert component which is added to the finished formulation other than the therapeutic ingredient.
The term xe2x80x9cnon-polar vehiclexe2x80x9d means a vehicle which has a dielectric constant of less than or equal to about 15.
The term xe2x80x9caprotic vehiclexe2x80x9d means a vehicle which does not contain acidic hydrogen (i.e., a hydrogen attached to an oxygen or nitrogen).
The term xe2x80x9canhydrous vehiclexe2x80x9d means a vehicle which does not contain water, including water adsorbed on its surface or combined as water of crystallization.
The terms xe2x80x9cvehicle with low reactivityxe2x80x9d and/or xe2x80x9clow-reactivity vehiclexe2x80x9d mean a vehicle which generally does not solubilize or otherwise react with proteinaceous compounds and/or nucleic acids. Low-reactivity vehicles are non-polar and have a Hildebrandt number of less than about 8.0. Examples of vehicles with low reactivity include: a) saturated hydrocarbons, b) halogenated saturated or unsaturated hydrocarbons, and c) esters and ethers of a) or b).
The terms xe2x80x9cproteinaceous particlexe2x80x9d and/or xe2x80x9cproteinaceous powderxe2x80x9d mean particles which contain proteins, proteinaceous compounds or proteinaceous substances. The proteinaceous particles of the present invention may, optionally, contain excipients, as defined above. Such excipients may include carbohydrates, non-ionic surfactants, buffers, salts, carrier proteins, preservatives and the like. However, the proteinaceous powders of the present invention do not contain polymers, nor are they encapsulated by polymeric materials (i.e., they are not microparticles or microcapsules as defined, for example, in U.S. Pat. No. 5,518,731).
The term xe2x80x9chydrationxe2x80x9d means water molecules associated with either the protein or nucleic acid, excipients or carriers.
The term xe2x80x9chydrophobicxe2x80x9d means incapable of dissolving to any appreciable extent in water.
The term xe2x80x9cnucleic acidxe2x80x9d means unbranched (linear or circular) chains of nucleotides in which the 5xe2x80x2 phosphoric group of each nucleotide is esterified with the 3xe2x80x2 hydroxyl of the adjoining nucleotide. The term includes ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) constructs. The term nucleic acid includes single and double stranded molecules, oligonucleotides, gene expression constructs, mRNA molecules, ribozymes, and the like. Naturally-derived or purified, synthetically produced and recombinantly produced moieties are all included in the term. The term also includes analogs, derivatives, and constructs that include promoter, leader, signal, polyadenylation or intron sequences, locus control regions, markers, and the like. Nucleic acids containing modified, derivatized or non-naturally occurring nucleotide units as part of their structure are also included in the term.
The terms xe2x80x9clipid/DNA complexxe2x80x9d and xe2x80x9clipid/RNA complexxe2x80x9d mean complexes that form between nucleic acids and small, cationic unilamellar vesicles held together by electrostatic interactions rather than by encapsulation of the nucleic acids in liposomes. A variety of topological arrangements can occur, such as DNA condensation, liposome aggregation and fusion.
The term xe2x80x9cliposomexe2x80x9d means the multi- or unilamellar vesicles formed from phospholipids which are used as carriers for drugs and macromolecules, especially nucleic acids.
The terms xe2x80x9cnucleic acid particlexe2x80x9d and/or xe2x80x9cnucleic acid powderxe2x80x9d mean particles which contain DNA or RNA. The nucleic acid may optionally be complexed with lipids or in liposomes, ribozymes, viral vectors, virosomes, dendrimers, cationic polymers, PLGA particles, or the like. The nucleic acid particles of the present invention may, optionally, contain excipients, as defined above. Such excipients may include carbohydrates, non-ionic surfactants, buffers, salts, carrier proteins, preservatives and the like.
B. Preparation of Formulations:
The present invention is drawn to non-aqueous formulations of proteinaceous particles and nucleic acid particles with less than about 10% hydration suspended in anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity, which formulations are stable for prolonged periods of time, even at elevated temperatures. Standard dilute aqueous peptide and protein formulations require manipulation of buffer type, ionic strength, pH and excipients (e.g., EDTA and ascorbic acid) to achieve stability. Standard nucleic acid formulations require formulation or reconstitution immediately prior to administration. In contrast, the claimed formulations achieve stabilization of protein or nucleic acid compounds by the use of dry particles and hydrophobic, anhydrous, non-polar, aprotic low-reactivity vehicles. In particular, stability and flowability of high concentrations (up to about 30%, w/w) of compound has been provided by the formulations of the present invention.
Examples of proteins and proteinaceous compounds which may be formulated using the present invention include those proteins which have biological activity or which may be used to treat a disease or other pathological condition. They include, but are not limited to growth hormone, Factor VIII, Factor IX and other coagulation factors, chymotrypsin, trypsinogen, alpha-interferon, beta-galactosidase, lactate dehydrogenase, growth factors, clotting factors, enzymes, immune response stimulators, cytokines, lymphokines, interferons, immunoglobulins, interleukins, peptides, somatostatin, somatotropin analogues, somatomedin-C, Gonadotropic releasing hormone, follicle stimulating hormone, luteinizing hormone, LHRH, LHRH analogues such as leuprolide, nafarelin and goserelin, LHRH agonists and antagonists, growth hormone releasing factor, calcitonin, colchicine, gonadotropins such as chorionic gonadotropin, oxytocin, octreotide, somatotropin plus an amino acid, vasopressin, adrenocorticotrophic hormone, epidermal growth factor, prolactin, somatotropin plus a protein, cosyntropin, lypressin, polypeptides such as thyrotropin releasing hormone, thyroid stimulation hormone, secretin, pancreozymin, enkephalin, glucagon, endocrine agents secreted internally and distributed by way of the bloodstream, and the like. Further agents that may be delivered include xcex11 antitrypsin, insulin and other peptide hormones, adrenal cortical stimulating hormone, thyroid stimulating hormone, and other pituitary hormones, interferon xcex1, xcex2, and xcex3, consensus interferon, erythropoietin, growth factors such as GCSF, GM-CSF, insulin-like growth factor 1, tissue plasminogen activator, CF4, dDAVP, tumor necrosis factor receptor, pancreatic enzymes, lactase, interleukin-1 receptor antagonist, interleukin-2, tumor suppresser proteins, cytotoxic proteins, retroviruses and other viruses, viral proteins, antibodies, recombinant antibodies, antibody fragments and the like.
Examples of nucleic acid compounds which may be formulated using the present invention include those nucleic acids which code for proteins which have biological activity or which may be used to treat a disease or other pathological condition, such as the protein compounds listed above. Nucleic acids, including sense or antisense oligonucleotides, which block or reduce production of unwanted proteins are also useful in the present invention. Also included in nucleic acids which may be used in the present invention are those which, either directly or by coding for a protein, stimulate an animal to produce immunity against a disease condition (e.g., cancer) or infection by a pathogenic organism such as a bacteria, virus or protozoa.
The above agents are useful for the treatment or prevention of a variety of conditions including but not limited to hemophilia and other blood disorders, growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditary diseases such as cerebrosidase deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as multiple sclerosis, Graves disease, systemic lupus erythematosus and rheumatoid arthritis, shock and wasting disorders, cystic fibrosis, lactose intolerance, Crohn""s disease, inflammatory bowel disease, gastrointestinal and other cancers. Analogs, derivatives, antagonists, agonists and pharmaceutically acceptable salts of the above may also be used.
The protein and nucleic acid compounds useful in the formulations and methods of the present invention can be used in the form of a salt, preferably a pharmaceutically acceptable salt. Useful salts are known to those of skill in the art and include salts with inorganic acids, organic acids, inorganic bases or organic bases. Nucleic acids may also be complexed with lipids or be presented as liposomes, ribozymes, viral vectors, virosomes, dendrimers, cationic polymers, PLGA particles, or the like.
The proportion of protein or nucleic acid may vary depending on the compound, the condition to be treated or prevented, the expected dose and the route and duration of administration. (See, for example, The Pharmacological Basis of Therapeutics, Gilman et al., 7th ed. (1985) and Pharmaceutical Sciences, Remington, 18th ed. (1990), the disclosures of which are incorporated herein by reference.) Applicable routes include oral, enteral, transdermal, percutaneous, parenteral, mucosal and the like, all of which are known to those of skill in the art. The concentration of protein or nucleic acid in high concentration formulations may range from at least about 1% (w/w) up to about 30% while still maintaining flowability. A preferred range for proteins is from about 10% to about 30% (w/w).
The vehicles useful in the present invention are non-aqueous, anhydrous, aprotic, non-polar, hydrophobic vehicles with low reactivity. Such vehicles have a dielectric constant less than or equal to about 15; do not contain acidic hydrogen, i.e., hydrogen attached to an oxygen or nitrogen; and generally do not solubilize or otherwise react with proteinaceous compounds. Preferred vehicles include: a) saturated hydrocarbons, b) halogenated saturated or unsaturated hydrocarbons, and c) esters and ethers of a) or b). Particularly preferred vehicles are perhalohydrocarbons and unsubstituted saturated hydrocarbons. Most preferred vehicles are biocompatible, such as perfluorodecalin, perflurobutylamine, perfluorotripropylamine, perfluoro-N-methyldecahydroquindine, perfluoro-octohydro quinolidine, perfluoro-N-cyclohexylpyrilidine, perfluoro-N,N-dimethylcyclohexyl methylamine, perfluoro-dimethyl-adamantane, perfluorotri-methylbicyclo (3.3.1) nonane, bis(perfluorohexyl) ethene, bis(perfluorobutyl) ethene, perfluoro-1-butyl-2-hexyl ethene, tetradecane, methoxyflurane or mineral oil.
The proteinaceous or nucleic acid powders useful in the present invention are solid particles wherein the hydration of the particle is less than about 10% (w/w water/compound). In contrast to previous protein formulations, where hydration and flexibility were required in order to maintain enzymatic activity, the proteins of the particles used in the present invention have minimal flexibility and minimal exposure to the degradative effects of moisture since protein hydration is minimized. In contrast to previous nucleic acid formulations, which required hydration in order to administer the formulation, the present formulations reduce hydration and degradation of the nucleic acid compounds while providing a flowable formulation suitable for administration. The powders may be produced by milling, spray drying, spray freeze-drying, lyophilization, precipitation, and the like. These protected powder particulates are preferably prepared using solid processing. They may optionally include protecting agents such as carbohydrates, sucrose, trehalose, sorbitol, raffinose, dextrans or cyclodextrins which may, for example, hydrogen bond to the proteins to reduce their effective hydration. They may also contain bulking agents such as glycine or mannitol that modify the morphology and/or processing characteristics of the proteins or nucleic acids, buffers that modify the pH, and non-ionic surfactants which protect from surface absorption and solubilize the protein or nucleic acids. The formulation of dry protein or nucleic acid powders is well known to those skilled in the art.
Here, protein or nucleic acid hydration refers to the fraction of the total moisture in a powder formulation associated with the protein or nucleic acid. Certain excipients (e.g., carbohydrates) reduce the amount of water associated with proteins [14] or nucleic acids. For purposes of this application, protein or nucleic acid hydration will be equal to the moisture content of the powder (determined, for example, by Karl Fischer analysis), expressed as a percentage, multiplied by the fractional weight of protein or nucleic acid in the powder.
Generally, the stable formulations of the present invention may be prepared by simply suspending the desired amount, which may be a therapeutically effective amount, of the desired proteinaceous or nucleic acid powder in the selected vehicle. Preferred vehicles include MO, PFD, MF, PTA and TD.
C. Methodology;
We have found that stable non-aqueous formulations of protein or nucleic acid compounds may be prepared by suspending dry (less than about 10% hydration) particles containing the protein or nucleic acid compound to be formulated in anhydrous, aprotic, hydrophobic, low-reactivity vehicle.
We have tested these formulations for stability by subjecting them to aging at elevated temperature (37xc2x0 C.) and measuring the chemical and/or physical stability of the formulations. Results of these studies (shown, for example, in Examples 1, 2 and 3) demonstrate that these formulations were stable for at least one month at 37xc2x0 C.
A major aspect of the invention is that the flowable non-aqueous formulations of the present invention are chemically and physically stable at high temperatures for long periods of time. Such formulations are stable even when high concentrations are used. Thus, these formulations are advantageous in that they may be shipped and stored at temperatures at or above room temperature for long periods of time. They are also suitable for use in implantable delivery devices.
The following method was used to perform the studies in the Examples that follow.
Karl Fischer Moisture Analysis: Vials and stoppers were dried overnight in a vacuum oven at 80xc2x0 C. Approximately 6 mg of sample was weighed into a dry vial and the vial was stoppered. Control vials were prepared by simply stoppering an empty dry vial (i.e., a vial containing no sample). Subsequently, 150 xcexcL aliquots of dry methanol was added to sample and control vials via a 250 xcexcL Hamilton Syringe (Hamilton Co., Reno, Nev.) which had been previously washed three times with dry methanol. The vials were then sonicated at room temperature until all solids were dispersed, centrifuged, and 100 xcexcL of the supernatant methanol was injected into an Aquatest 10 Coulometric Moisture Analyzer (SeraDyn Inc., Indianapolis, Ind.). The resultant readings were recorded, and water content of the sample calculated by subtracting the control reading from that of the sample.
The following reagents were used to perform the studies in the Examples that follow.
Perfluorodecalin, perfluorotributylamine and tetradecane were purchased from Aldrich Chemical Company (Milwaukee, Wis.). Methoxyflurane was purchased from Abbott Laboratories (North Chicago, Ill.). Light Mineral Oil USP was purchased from Spectrum Chemical Corp. (Gardena, Calif.).
The following examples are offered to illustrate this invention and are not meant to be construed in any way as limiting the scope of this invention.

Stable protein and nucleic acid formulations using non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity


A transfer surface of an intermediate transfer member is treated using an electrical discharge surface treatment. The intermediate transfer member is comprised in a printing apparatus.

Liquid electrophotographic printing, also referred to as liquid electrostatic printing, uses liquid toner to form images on a print medium. A liquid electrophotographic printer may use digitally controlled lasers to create a latent image in the charged surface of an imaging element such as a photo imaging plate (PIP). In this process, a uniform static electric charge is applied to the photo imaging plate and the lasers dissipate charge in certain areas creating the latent image in the form of an invisible electrostatic charge pattern conforming to one colour separation of the image to be printed. An electrically charged printing substance, in the form of liquid toner, is then applied and attracted to the partially-charged surface of the photo imaging plate, recreating a separation of the image.
In some liquid electrophotographic printers, a transfer member, such as an intermediate transfer member (ITM) is used to transfer developed liquid toner to a print medium. For example, a developed image, comprising liquid toner aligned according to a latent image, may be transferred from the photo imaging plate to a transfer blanket of the intermediate transfer member. From the intermediate transfer member, the toner is transferred to a substrate, which is placed into contact with the transfer blanket.


A connector terminal which can achieve high mechanical connection strength and stabilized low electrical connection resistance when it is crimped to an aluminum electric wire, and in addition, can suppress electrical contact resistance low when it is fitted to a mating connector terminal is provided. In a connector terminal (1A) having an electrical contact section (10) which is brought into contact and conducted with a mating connector terminal by fitting to the mating connector terminal, and a conductor crimping section (12) which is crimped to the conductor of an electric wire, a metal material which constitutes the terminal uses aluminum or an aluminum alloy as a base material (100), a Zn layer (101) having a thickness in the range from 0.1 μm to 2.0 μm by electroless plating and a Cu layer (102) having a thickness in the range from 0.5 μm to 1.0 μm by electrolytic plating are formed in sequence on the surface of the base material (100), and an Sn layer (105) having a thickness in the range from 0.7 μm to 1.7 μm by electrolytic plating is formed on the outermost surface.

Connector terminal generally used in a connector is constituted of a metallic material including copper (Cu) or a copper (Cu) alloy, having tin (Sn) plated thereon, and has an electrical contact section which is brought into contact and conducted with a mating connector terminal by fitting to the mating connector terminal in a front section thereof and a conductor crimping section which is crimped to a conductor of an electric wire at a rear section thereof.
The reason for applying Sn plating to the surface of a terminal base material is that Sn is very soft, spontaneous oxide coating of Sn can easily be mechanically destroyed by contact load between terminals in fitting connector terminals to each other, newly-formed surfaces of Sn can be contacted to each other, and as a result, good contact performance (that is, low and stabilized contact resistance) can stably be maintained over a long period of time.
Where the Sn plated layer is not present, an oxide coating of a hard copper (or copper alloy) base material appears on the surface, and as a result, mechanical destruction of the surface layer at the time of fitting a terminal to the base material cannot be expected. Furthermore, because the oxide coating of copper has very high volume resistivity, contact resistance between terminals is apt to become high.
By the way, recently an aluminum electric wire begun to be used in place of a copper electric wire even in the field of electric wire harness for automobiles for the purpose of reduction in weight and improvement in recycle property. The aluminum electric wire is an electric wire having an aluminum-made or aluminum alloy-made conductor section.
In the case of using the aluminum electric wire, crimping of a terminal particularly becomes a problem.
In the case that the conductor crimping part of the connector terminal is crimped to an aluminum (or aluminum alloy) core of the aluminum electric wire, electrical resistance of the crimping connection part is apt to become high due to, for example, difference in springback properties and difference in coefficient of thermal expansion, between aluminum (or aluminum alloy) and copper (or copper alloy). For this reason, in the case of crimping a copper terminal to an aluminum electric wire, overcrimping stronger than the general crimping is performed in order to suppress electrical resistance low. The overcrimping is a manner of crimping in which compressibility is large as compared with the case of crimping a copper terminal to a copper electric wire, and is that, for example, conductor compressibility is 60% or less.
However, the case that overcrimping has been performed gives rise to the problem that the core of an electric wire is too compressed, and as a result, in the case of receiving tensile load in an axial direction, the electric wire becomes easy to be broken in the crimping section (that is, decrease in strength in crimping section).
In view of the above, for example, in a crimp structure shown in Patent Document 1, as shown in FIG. 7, difference in level for separating a front side part and a rear side part is provided on a conductor crimp section 212 of a connector terminal 200, a terminal is weakly crimped to an aluminum electric wire in a crimping section 212a at a rear side (that is, with conductor compressibility to the same extent as the case to a copper wire), and is strongly crimped to an aluminum electric wire in a crimping section 212b at a front side (that is, with large conductor compressibility). Thus, by performing the crimping in two stages, both electrical connection performance and mechanical connection performance are attempted to achieve. At the front side of the conductor crimping section 212, an electrical contact section 210 which is brought into contact and conducted with a mating connector terminal by fitting to the mating connector terminal is provided, and at the rear side of the conductor crimping section 212, a covering swage section 213 swaged to an insulating cover-attached section of an electric wire W.


Information describing one or more items is published to multiple subscribers. A subsequent change to the information requested by one of the multiple subscribers (such as a change in the status of an item corresponding to the information) is communicated to each of subscribers to which the information was previously published.

As computing technology has advanced, computers have become increasingly coupled together via various networks. This increased ability to communicate with other computers provides many advantages, allowing data to be quickly communicated to friends, colleagues, or even strangers throughout the world.
One specific use of this increased communication ability is for the sale of goods. Individual companies can make their goods available for sale over a network, such as the Internet, allowing individual users to view descriptions of, and purchase, the goods at their leisure. Additionally, on-line auction houses have also been established, allowing individual users to list various goods for sale and allow other users to bid on those goods.
However, problems exist in attempting to use these mechanisms for the sale of goods in environments where multiple different sellers attempt to sell the same good. Mechanisms to support the offer for sale of the same good by multiple different sellers and to ensure accurate and up-to-date information regarding the goods (e.g., whether the good has been sold by one of the sellers) do not currently exist. It would thus be desirable to have a technique to improve the ability of multiple different sellers to offer the same good for sale.

Maintaining synchronization of information published to multiple subscribers


The invention provides a transient voltage detecting circuit for detecting a transient voltage occurring at a power supply or a ground of an electronic system. The circuit according to the invention includes a plurality of detecting units of which the outputs are initially latched by at least one voltage source. The circuit also includes a detecting device outputting a first logic according to the initial outputs of all of the detecting units. When the transient voltage occurs, it is ensured that the logic of the output of one of the detecting units is changed by the transient voltage or the decayed transient voltage, such that the decision device renewably outputs a second logic to trigger a resetting device of the electronic system in accordance with the outputs of all of the detecting units.

1. Field of the Invention
The present invention relates to a transient voltage detection circuit, especially to a transient voltage detection circuit in an electronic system capable of triggering a resetting device of the electronic system.
2. Description of the Prior Art
If a protection device is not installed in a common electronic system, while the electronic system is operating, the voltage thereof will be unstable due to external interference or the electromagnetic effect of the elements in the circuit board; thus, each element in the circuit will be forced to function under the environment of an unstable voltage, possibly causing an error in the system, a systemic crash, or even damage of elements. To solve the above problem, the prior art installs a manual reset device in the circuit, e.g. an electric switch with a button, so that a user, according to his/her experience, may judge whether the reset device should be driven to reset the electronic system.
An automatic reset circuit with the function of detecting transient voltage variation is disclosed in U.S. Pat. No. 5,999,392. The automatic reset circuit is used for detecting the transient voltage variation between the power supply and the ground, so as to reset the electronic system immediately. According to the invention, when a transient interference or disturbance occurs between the power supply and the ground in the circuit, the system can be reset immediately to avoid abnormal functioning of the elements in the circuit.
The detecting unit revealed in U.S. Pat. No. 5,999,392 detects the transient voltage variation by the manner of voltage-couple, and it occupies a larger area, so it is not suitable for small electronic apparatus, e.g. personal digital assistant (PDA), mobile phone, and so on. Moreover, while a transient voltage variation occurs between the power supply and the ground, damping will occur in the voltage of the power supply or the ground with time and space. Because the detecting unit itself also needs appropriate power to maintain normal operation, when a transient voltage variation occurs between the power supply and the ground, damping will also occur in the voltage of the power supply or the ground connecting to the above detecting unit. At this moment, the state of the detecting unit is difficult to be predicted, and it is difficult to predict whether the detecting unit can operate accurately in accordance with the design of which the voltage is under normal condition. In other words, when a transient voltage variation occurs between the power supply and the ground, it cannot be confirmed whether the detecting unit will work as if the voltage is normal. Thus, it is difficult for the above automatic reset device with the function of detecting transient voltage variation to achieve the expected function. In other words, although there is a transient voltage variation, the detecting unit may not detect it and maintains the original state. The behavior of the detecting unit is related to the position thereof and the manner of power damping, so the effect of power damping will be different if the detecting unit is located at different positions of the circuit. Therefore, the detection function of the detecting unit of the prior art is limited.
Therefore, the objective of the present invention is to provide a transient voltage detection circuit to solve the above problem.


A liquid crystal display device includes first and second substrates spaced apart from and facing each other, gate and data lines on an inner surface of the first substrate and crossing each other to define a pixel region, a thin film transistor adjacent to the crossing of the gate and data lines, a pixel electrode in the pixel region and including a plurality of slits, an island pattern over the gate line, a black matrix on an inner surface of the second substrate, the black matrix corresponding to the gate line, a color filter layer on the black matrix, a common electrode on the color filter layer, a plurality of ribs on the common electrode corresponding to the pixel electrode; and a spacer on the common electrode corresponding to the black matrix.

1. Field of the Invention
The present invention relates to a display device, and more particularly, to a liquid crystal display device and a method of fabricating the same.
2. Discussion of the Related Art
Liquid crystal display (LCD) devices are driven so as to use the optical anisotropy and polarization characteristics of a liquid crystal material. More particularly, liquid crystal molecules have a definite alignment as a result of their long, thin shapes and are arranged to have initial pre-tilt angles. The alignment direction can be controlled by applying an electric field. Accordingly, variations in an applied electric field influence the alignment of the liquid crystal molecules. Due to optical anisotropy of the liquid crystal molecules, the refraction of incident light depends on the alignment direction of the liquid crystal molecules. Thus, by properly controlling the applied electric field, an image that has a desired brightness can be produced.
FIG. 1A is a perspective view schematically illustrating a related art LCD device, and FIG. 1B is an enlarged view of a thin film transistor T in FIG. 1A. As shown in FIGS. 1A and 1B, the LCD device 51 includes a first substrate 22 and a second substrate 5, which are spaced apart from each other, and a liquid crystal layer 11 (not shown) interposed between the first substrate 22 and second substrate 5. A black matrix 6, a color filter layer 7, and a common electrode 9 are formed on an interior surface of the second substrate 5, which faces the first substrate 22. The color filter layer 7 includes red, green and blue color filters 7a, 7b and 7c, each of which is disposed in an opening of the black matrix 6. The common electrode 9 is transparent and covers the black matrix 6 and the color filters 7a, 7b and 7c.
A plurality of pixel regions P are defined on an interior surface of the first substrate 22, which faces the second substrate 5. A plurality of gate lines 12 and a plurality of data lines 24 cross each other to define the plurality of pixel regions P. A thin film transistor T is formed adjacent to where the gate and data lines 12 and 24 cross each other. The thin film transistor T includes a gate electrode 30, an active layer 32, a source electrode 34, and a drain electrode 36. The active layer 32 overlaps the gate electrode 32, and the source and drain electrodes 34 and 36 are spaced apart from each other and positioned over the active layer 32. A pixel electrode 17 is formed in each pixel region P and is connected to the drain electrode 36 of the thin film transistor T in each pixel region P. The pixel electrode 17 includes a transparent conductive material having high transmittance, such as indium-tin-oxide (ITO) or indium-zinc-oxide (IZO). The thin film transistor T and the pixel electrode 17 of each pixel are arranged in a matrix form. Pulse signals are provided to the gate electrode 30 through the gate line 12, and data signals are provided to the source electrode 34 through the data line 24.
The second substrate 5 including the black matrix 6, the color filter layer 7 and the common electrode 9 is often referred to as a color filter substrate. The first substrate 22 including the gate lines 12, the data lines 24, the thin film transistors T and the pixel electrodes 17 is often referred to as an array substrate.
In the above related art LCD device, various approaches have been researched for achieving wide viewing angles and high brightness. A multi-domain method, a phase compensation method, an in-plane switching (IPS) mode, a vertical alignment (VA) mode, and so on have been researched and developed as methods for achieving wide viewing angles. In the multi-domain method, a pixel is divided into several regions, in which each of the liquid crystal molecules are differently arranged so that each pixel has overall average properties. In the phase compensation method, a phase difference film, which is often referred to as a retardation film, is used to reduce changes in phase difference depending on viewing angles. In the IPS mode, liquid crystal molecules move in a plane substantially parallel to the substrates corresponding to an electric field produced in parallel to the substrate of the LCD device. In the VA mode, liquid crystal molecules having negative dielectric anisotropy are arranged vertically with respect to the substrate when voltage is not applied.
Among the above methods, the VA mode has the additional advantage of fast response time as compared to the twisted nematic (TN) mode, which is widely used in conventional LCD devices. The VA mode has a response time of about 30 ms as compared with the 50 ms of the TN mode, when the transmittance of the LCD device changes from 100% to 50%. Generally, in the VA mode, a vertical alignment material, a liquid crystal material with negative dielectric anisotropy and a negative retardation film are used. Thus, the VA mode has a wide viewing angle, and has a high contrast ratio.
FIG. 2 is a cross-section view illustrating a pixel region of a VA mode LCD device according to the related art. As shown in FIG. 2, a pixel electrode 17 is formed on an interior surface of a first substrate 22, and a black matrix 6, a color filter layer 7 and a common electrode 9 are subsequently formed on an interior surface of a second substrate 5, which is spaced apart from and facing the first substrate 22. A liquid crystal layer 11 is interposed between the first and second substrates 22 and 5. The liquid crystal layer 11 has a negative dielectric anisotropy, and liquid crystal molecules of the liquid crystal layer 11 may be vertically arranged between the first and second substrates 22 and 5.
When a voltage is applied to the pixel electrode 17 and the common electrode 9, an electric field E substantially perpendicular to the substrates 5 and 22 is induced between the pixel electrode 17 and the common electrode 9, and the liquid crystal molecules of the liquid crystal layer 11 are realigned so as to be perpendicular with respect to the direction of the electric field E. At this time, the pixel electrode 17 is partially patterned and has slits S (or holes), and the electric field E is distorted due to the slits S. Thus, multi-domains are formed in one pixel region. Further, a rib is formed on the common electrode 9 at a center portion between the slits S of the pixel electrode 17, and the pixel region may be symmetrically divided so as to have mirrored patterns or the same patterns at upper and lower parts of the pixel electrode 17. Meanwhile, a spacer SP is further formed on the common electrode 9 to maintain a cell gap between the first and second substrates 22 and 5.
FIGS. 3A to 3D are cross-sectional views illustrating a manufacturing method of a color filter substrate for a related art VA mode LCD. As shown in FIG. 3A, a black matrix 6 is formed on a transparent substrate 5 by coating a black resin and then patterning the black resin through a first mask process, or by depositing either chromium (Cr) or chromium oxide (CrOX) and then patterning one of the chromium layers through a first mask process. The black matrix 6 may be in a variety of shapes depending on the structure of an array substrate (not shown). However, the black matrix typically has a lattice shape.
As shown in FIG. 3B, a color filter layer 7 is formed on the substrate 5, including the black matrix 6. The color filter layer 7 includes red, green and blue color filters. The color filter layer 7 may be formed through one of various methods. A pigment dispersion method is widely used for forming the color filter layer 7. In the pigment dispersion method, each color filter can be formed by coating a pigment resin across a surface of the transparent substrate 5 and then patterning the pigment resin through a mask process. Accordingly, the color filter layer 7 having three colors can be formed through a three mask process, such as second, third and fourth mask processes.
As shown in FIG. 3C, a common electrode 9 is formed across the surface of the substrate 5, including the color filter layer 7. Subsequently, a rib R is formed on the common electrode 9 by coating a resin and then patterning the resin through a fifth mask process. As shown in FIG. 3D, a spacer SP having a columnar shape is formed on the substrate 5 by coating a polymer resin and then patterning the polymer resin through a sixth mask process. The spacer SP corresponds to the black matrix 6. The color filter substrate for the VA mode LCD device, including the spacer SP and the rib R, is manufactured using six mask processes. Thus, the color filter substrate for this related art VA mode LCD device has two additional mask processes for the rib and the spacer as compared to a color filter substrate for a related art TN mode LCD device, which is manufactured using four mask processes. Accordingly, manufacturing time and costs are higher for a VA mode LCD, and thus productivity is lower.
To improve productivity, a process for simultaneously forming the rib and the spacer has been proposed. FIGS. 4A to 4C are cross-sectional views illustrating a manufacturing method of another color filter substrate for another related art VA mode LCD device. As shown in FIG. 4A, a black matrix 52 is formed on a transparent substrate 50, on which pixel regions P are defined, by coating a black resin and then patterning the black resin through a first mask process.
As shown in FIG. 4B, a color filter layer is formed on the substrate 50, including the black matrix 52. The color filter layer includes red 54a, green 54b and blue (not shown) color filters. The red, green and blue color filters can be formed through second, third and fourth mask processes, respectively. This masking process yields color filters that overlap each other. For example, the red and green color filters 54a and 54b, are sequentially formed such that they both overlap the black matrix 50 and the green color filter 54b overlaps the red color filter 54a. A subsequent blue color filter (not shown) would overlap the black matrix 50 and both of the red and green color filters 54a and 54b. Accordingly, the combined thickness of the black matrix 52, the red color filter 54a and the green color filter 54b is thicker than a thickness of each of the color filters in the pixel regions P.
As shown in FIG. 4C, a common electrode 56 is formed across a surface of the substrate 50, including the color filter layer. A first rib R1 and a second rib R2 are formed on the common electrode 56 by coating a resin and then patterning it through a fifth mask process. The first rib R1 is disposed over where the green color filter 54b, the red color filter 54a, and the black matrix 52 are sequentially overlapped, and the second rib R2 is disposed in each pixel region P. The first rib R1 together with the overlapped color filters 54a and 54b functions as a spacer, and the second rib R2 is used to form multi domains in one pixel region. A total thickness H of the first rib R1 and the overlapped color filters 54a and 54b may be about 4 μm. Accordingly, a color filter substrate may be manufactured through a five mask process, which is less than the six mask manufacturing processes for a color filter substrate shown in FIGS. 3A to 3D. However, the common electrode 56 in the five mask color filter substrate may be disconnected due to a step coverage (or difference) created by the overlapping color filters on the black matrix.

Liquid crystal display device and method of fabricating the same


The invention relates to an arrangement for transporting radicals. The arrangement includes a plasma generator and a guiding body. The plasma generator includes a chamber (2) in which a plasma may be formed. The chamber has an inlet (5) for receiving an input gas, and one or more outlets (6) for removal of at least one of the plasma and radicals created therein. The guiding body is hollow and is arranged for guiding radicals formed in the plasma towards an area or volume at which contaminant deposition is to be removed. The chamber inlet is coupled to a pressure device (40) for providing a pulsed pressure into the chamber so as to create a flow in the guiding body.

1. Field of the Invention
The invention relates to an arrangement and method for transporting radicals, for example for removal of contaminant deposits. The invention further relates to a charged particle lithography system comprising such arrangement. The invention further relates to a pressure regulator for connection to a plasma chamber. The invention further relates to a method for transporting radicals.
2. Description of the Related Art
The accuracy and reliability of charged particle lithography systems is negatively influenced by contamination. An important contribution to contamination in such lithography system is caused by the build-up of deposits of contaminants. The charged particles being part of the patterning beamlets and being produced in the system interact with hydrocarbons already present in the system. The resulting Electron Beam Induced Deposition (EBID) forms a carbon containing layer on surface in the system. This layer of carbon containing material influences beam stability. Build-up of such carbon containing layer in and around apertures through which the charged particle beams and/or beamlets pass also reduces the size of the apertures and reduces transmission of beams or beamlets through these apertures. Removal of EBID, in particular in areas with relatively high hydrocarbon partial pressures and relatively high beam current densities, is therefore highly desirable.
Such deposits can be reduced or removed by atom cleaning. This may be achieved using a plasma generator to produce a stream of atoms to react with the deposits. The transport of plasma and the atoms provided therein, in particular radicals, is often inefficient, which may lead to relatively long cleaning periods, and insufficient cleaning quality, i.e. incomplete or inadequate removal of contaminants on a specific surface or a specific volume.

Arrangement and method for transporting radicals


Methods for fabricating alternating phase shift masks or reticles used in semiconductor optical lithography systems. The methods generally include forming a layer of phase shift mask material on a handle substrate and patterning the layer to define recessed phase shift windows. The patterned layer is transferred from the handle wafer to a mask blank. The depth of the phase shift windows is determined by the thickness of the layer of phase shift mask material and is independent of the patterning process. In particular, the depth of the phase shift windows is not dependent upon the etch rate uniformity of an etch process across a surface of a mask blank.

As feature sizes and pitches shrink in the fabrication of integrated circuit devices, the resolution of the projection optics in conventional optical lithography systems begins to limit the quality of photoresist images created on wafers using binary photomasks that only modulate the intensity of the projected electromagnetic radiation. Specifically, electromagnetic radiation from a light source of the optical lithography system is completely blocked by the opaque features in the binary mask and is fully transmitted through transparent mask regions. Alternating phase shift masks (altPSM's) represent a powerful resolution enhancement technique (RET) that can effectively increase the resolution of conventional optical lithography systems by introducing a 180° or half-wavelength phase shift in the light transmitted between neighboring windows of the mask. This phase shifting is accomplished by creating a path length difference for the exposing electromagnetic radiation in the mask material between adjacent windows on the phase shift mask. Features are formed in exposed resist by the diffraction edges due to destructive interference. Hence, altPSM's not only modulate the intensity of the transmitted electromagnetic radiation, but its phase as well.
The optical path length difference is created by recessing phase shift windows in a blank of the transparent mask material to a depth proportional to the source wavelength and inversely proportional to the refractive index of the mask material. The mask blank is typically fabricated by patterning a layer of an opaque material deposited on the mask blank and then providing recessed phase shift windows in the unmasked areas of the patterned opaque layer by reactive ion etching (RIE). The fabrication of altPSM's is limited by the uniformity of the etch process. Specifically, the mask blank lacks an etch stop layer so that the inherent pattern factor and across-wafer substrate spatial variations of the etch rate in the RIE process chamber are reproduced in the mask blank. The variations in etch depth arising from the etch rate variations degrade depth of focus and effectively reduce resolution in the finished altPSM as the phase shift windows have different depths in different regions of the altPSM.
What is needed, therefore, is a method of fabricating an alternating phase shift mask that forms phase shift windows without directly etching a mask blank.

Methods of forming alternating phase shift masks having improved phase-shift tolerance

International Business Machines Corporation


Techniques for providing improved perpetrator imaging are disclosed. In one particular exemplary embodiment, the techniques may be realized as a method for providing improved perpetrator imaging comprising identifying a client device as at least one of lost and stolen, detecting, on the client device, a difference in first pixel data associated with a first frame of a visual image and second pixel data associated with a second frame of the visual image, and capturing, on the client device, a plurality of photographs in response to detecting the difference.

The consumer and commercial use of mobile devices (e.g., laptops, mobile phones, tablet personal computers (PCs), net-books, personal digital assistants (PDAs)) is rapidly increasing. Likewise, mobile device theft has also increased with the increase in mobile device use. Accordingly, many mobile devices are manufactured with certain anti-theft mechanisms. Many anti-theft mechanisms currently used, however, operate inefficiently and are ineffective.
In view of the foregoing, it may be understood that there may be significant problems and shortcomings associated with current anti-theft technologies.


Compounds containing at least one tetraketopiperazine-1,4-diyl unit are disclosed as active materials in the positive electrodes of batteries. Novel methods for preparing the tetraketopiperazine unit-containing compounds include: (i) reacting an oxalyl halide and an oxamide, and adding water or an aqueous alkali solution to the reaction mixture, (ii) reacting an oxalyl halide and a silylamine, (iii) reacting an oximidyl halide and an amine, (iv) reacting an oxalyl halide and a silylamine, and reacting with an amine, (v) reacting an oxalyl halide and a dioxamide, (vi) reacting an oximidyl halide and a diamine, and (vii) reacting an oxalyl halide and a silylamine, and reacting with a diamine. A novel method for preparing an oximidyl halide is also disclosed.

The invention relates generally to a use of tetraketopiperazine unit-containing compounds as active ingredients in the positive electrodes of batteries and to methods for preparing the tetraketopiperazine unit-containing compounds.
Batteries play an important role within industrialized society. It is estimated that on average ten batteries are used by every person in the United States every year. The economic and environmental impact of this usage is staggering and represents a major point of interest for those in and outside the art.
A battery, in general, is an electrochemical device that generates electric current by converting chemical energy to electrical energy. The essential components of a battery include the positive and negative electrode, a separating medium and an electrolyte. In general, chemically active materials at the negative electrode are oxidized to release electrons which travel to the positive electrode, creating a useable current, where they reduce chemically active materials at the positive electrode. The separating medium keeps the two electrodes insulated from each other, while the electrolyte maintains the oxidizing environment at the negative electrode and the reducing environment at the positive electrode.
Presently, most batteries rely upon chemically active materials that contain metal oxide compounds, due to their excellent oxidizing and reducing capabilities. The metal oxide compounds typically contain manganese, cobalt, nickel, lead, silver, mercury, and the like. Unfortunately, especially in relation to non-rechargeable batteries, or primary batteries, the use of metal oxides represents a large scale environmental problem, where production and disposal of the batteries may result in the release of heavy metals into the environment.
For at least these reasons, there has been an emphasis on developing active materials that limit the use of metal oxides in the electrodes, and in particular, developing organic materials to replace the metal oxides. However, organic materials have proven expensive to produce in the large quantities required for use in battery applications, and have failed to show the requisite electric capacity needed in most battery applications. Synthesis Metals, 1987, 259-264. Against this backdrop the present invention has been developed.
Embodiments of the present invention are directed at novel uses of a compound having at least one tetraketopiperazine-1,4-diyl unit, as represented by formula (1), as an active material in the positive electrodes of batteries.
Preferable embodiments of the present invention are directed at novel uses of the compound, where the compound has one or two tetraketopiperazine-1,4-diyl units as the active material in the positive electrodes of batteries.
Other embodiments of the present invention are directed at novel uses of a -mono(tetraketopiperazine) compound and di(tetraketopiperazine) compound represented by formulas (1-1) and (1-2), respectively, as active materials in the positive electrodes of batteries.
R1 and R2 are independently a hydrogen atom or a substituted or unsubstituted alkyl or aryl group.
R1 and R2 are defined as above and A is a substituted or unsubstituted alkylene or arylene group.
Method A
Other embodiments of the present invention are directed at methods for preparing mono(tetraketopiperazine) compound as represented by formula (1-1) above, by reacting an oxalyl halide represented by formula (2) and an oxamide represented by formula (3), and adding water or an aqueous alkali solution to the reaction mixture. The addition of water or an aqueous alkali solution provides for a substantial increase in the yield of the tetraketopiperazine compound.
X1xe2x80x94COCOxe2x80x94X2xe2x80x83xe2x80x83Formula (2)
The X1 and X2 are independently a halogen atom.
R1xe2x80x94NHxe2x80x94COCOxe2x80x94NHxe2x80x94R2xe2x80x83xe2x80x83Formula (3)
The R1 and R2 are defined as above.
Method B
In another embodiment of the present invention, the mono(tetraketopiperazine) compound represented by formula (1-1) above is prepared by reacting an oxalyl halide represented by formula (2) above and a silylamine represented by formula (4).
R1 is defined as above and R3, R4, R5, R6, R7 and R8 are independently a substituted or unsubstituted alkyl or aryl group.
Method C
In another embodiment of the present invention, the mono(tetraketopiperazine) compound represented by formula (1-1) above is prepared by reacting an oximidyl halide represented by formula (5) and an amine represented by formula (6).
R1, X1, and X2 are defined as above.
R2 is defined as above, and Y1 and Y2 are independently a hydrogen atom, SiR3R4R5, or SiR6R7R8, in which R3, R4, R5, R6, R7 and R8 are independently a substituted or unsubstituted alkyl or aryl group.
Method D
In another embodiment of the present invention, the mono(tetraketopiperazine) compound represented by formula (1-1) above is prepared by reacting an oxalyl halide represented by formula (2) above and a silylamine represented by formula (4) above, and reacting with an amine represented by formula (6) above.
Method E
In another embodiment of the present invention, a di(tetraketopiperazine) compound represented by formula (1-2) above is prepared by reacting an oxalyl halide represented by formula (2) above and a dioxamide represented by formula (7), and, preferably, adding water or an aqueous alkali solution to the reaction mixture.
R1xe2x80x94NHxe2x80x94COCOxe2x80x94NHxe2x80x94Axe2x80x94NHxe2x80x94COCOxe2x80x94NHxe2x80x94R2xe2x80x83xe2x80x83Formula (7)
R1, R2 and A are defined as above.
Method F
In another embodiment of the present invention, the di(tetraketopiperazine) compound represented by formula (1-2) above is prepared by reacting an oximidyl halide represented by formula (5) above and a diamine represented by formula (8).
A is defined as above, and Y1, Y2, Y3, and Y4 are independently a hydrogen atom, SiR3R4R5, SiR6R7R8, SiR9R10R11, or SiR12R13R14, in which R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are independently a substituted or unsubstituted alkyl or aryl group.
Method G
In another embodiment of the present invention, the di(tetraketopiperazine) compound represented by formula (1-2) above is prepared by reacting an oxalyl halide represented by formula (2) above and a silylamine represented by formula (4) above, and reacting with a diamine represented by formula (8) above.
Finally, in another embodiment of the present invention, oximidyl halide represented by formula (5) above is prepared by reacting an oxalyl halide represented by formula (2) above with a silylamine represented by formula (4) above. The oximidyl halide of formula (5) above is an important intermediate for preparing the mono- and di(tetraketopiperazine) compounds represented by formulas (1-1) and (1-2) above.
Other embodiments of the present invention relates to new compounds produced by the methods of the present invention, which include N,Nxe2x80x2-diethyl-2,3,5,6-tetraketopiperazine, N-alkyl-Nxe2x80x2-aryl-2,3,5,6-tetraketopiperazine, and the di(tetraketopiperazine) compounds represented by formula (1-2) above.
These and various other features as well as advantages which characterize the invention will be apparent from a reading of the following detailed description and a review of the appended claims.

Tetraketopiperazine unit-containing compound as an active material in batteries


Apparatus for superimposing graphic title image signals onto an input video signal to produce a video picture having graphics, such as title images, superimposed thereon. Graphic title image data is written into a memory and subsequently is read out under the control of an address generator whose read-out addresses are shifted at a given repetition rate to change the positioning of the graphic title image data relative to the video signal, thereby producing a scrolling effect of the graphics across an image plane.

1 Field of the Invention
This invention relates to apparatus for superimposing graphic title image signals (or other graphics) onto a video signal and for causing such superimposed images to scroll across the video picture derived from the video signal This invention finds ready application in so-called video titlers and telopers (or opaque projectors) and is particularly useful with video cameras of the type having an image pick-up device and a video tape recorder (VTR) housed within the same housing.
1. Description of Background Art
Apparatus for superimposing graphic title images onto video signals have been developed as peripheral equipment for use with VTR's. Such graphic title images, referred to generally as graphics, are used in video dubbing to superimpose, or insert, graphic data onto a recorded video signal. As a result, a composite video signal containing graphic information is recorded Such peripheral equipment is known to the prior art as titlers or telopers for dubbing graphic information, usually titles, onto the recorded video signals.
Typical of such graphic inserting equipment are character generators which are capable of generating various types of alphanumeric patterns. The patterns formed by such character generators appear as title image signals and are superimposed onto video signals that are reproduced from the VTR or that may be derived from an image pick-up device. However, such character generators usually are not suited for integration with presently available video cameras. A conventional video camera is a hand-held device containing a VTR and an image pick-up section within the same housing. Character generators usually are too large, too heavy and too expensive to be integrated into such video cameras.
It has been proposed to provide video cameras with the capability of inserting graphics, such as graphic title image data, into the video signals generated by the image pick-up section. One suggestion is to use the image pick-up section to image graphics which, for example, may be drawn on a screen, poster, placard, or the like, thereby generating video signals corresponding to the imaged graphics, and then storing this graphic data in a suitable memory provided in the video camera. Thereafter, the stored graphic data may be read from the memory and superimposed onto the video signal then being generated by the image pick-up section (such as the video signal representing a scene being "photographed" by the image pick-up section). The video signal then being imaged, together with the superimposed graphic data may be recorded by the VTR section of the video camera.
The graphic insertion proposal of the type just described writes graphic data into the memory on a line-by-line basis, with each line generally being divided into several image units, analogous to pixels. The location of the graphic data that is read from the memory, relative to a picture image plane, is, of course, substantially identical to the location of that graphic data when it was written into the memory. Thus, if graphic material occupied the center portion of the image plane when it was written into the memory, the graphics read from the memory and superimposed onto an input video signal likewise will occupy the center portion of the image plane. Similarly, original graphics data disposed at the bottom or top of the image plane when written into the memory will occupy the bottom or top of that same image plane when read. Likewise, graphics data located to the left or right of the image plane when written will be superimposed to the left or right of the image plane when read. Thus, the particular position of the graphic data that is imaged by the pick-up section remains fixed when that graphic data subsequently is superimposed onto another video signal imaged by the pick-up section. The user of the video camera is provided with limited flexibility in adjusting the position of the graphic data after that data has been imaged and stored in the memory. Accordingly, a noted drawback of graphic insertion apparatus of the type described above is that the graphic data that is stored in the memory cannot subsequently be scrolled horizontally or vertically, relative to a video picture, or video image plane.


A thin sheet of metal foil is inserted in a typewriter and conventional typing strokes produce indentations therein. The ribbon of the typewriter contains material of a high degree of visibility which is deposited at the bottom of the indentations. A fixative ensures that the material is properly disposed in place. The sheet is mounted on a base and a layer of clear plastic is provided around the plaque. The plaque is removably mounted on a coffin by a pair of pins or brackets each of which includes portions disposed at an angle of about 45.degree. to one another. Attaching means including a bracelet secures the plaque to the remains within the coffin.

The present invention relates to a plaque and method of making same, and more particularly to a plaque especially suited for use with a coffin and human remains disposed in a coffin to provide identification of the deceased and also suitable biographical information or an epitaph concerning the deceased. While designed primarily for use with human remains, the plaque may also be used, for example, with pets.
A plaque for the purpose of the invention must provide the information in such a manner that it may be easily read by observers at a viewing or a funeral. When the plaque is mounted on a coffin, persons standing next to the coffin can read the information, thereby placing such persons at ease and providing a suitable topic of conversation.
Plaques utilized for this purpose are designed to provide a permanent record of identification for posterity, and accordingly should be manufactured of materials which are virtually indestructible whereby the information thereon will be discernible far into the future. Plaques made of materials similar to the present invention are shown in U.S. Pat. Nos. 4,332,074 and 4,481,160. These patents disclose constructions employing decorative metal foil which is embossed and embedded in a clear plastic substance to protect the foil.
Means are provided for readily mounting and removing the plaque with respect to a coffin, while supporting the plaque in desired reading position when the plaque is mounted on the coffin. Furthermore, means are provided for permanently securing the plaque to the remains in the coffin subsequent to the funeral ceremony and prior to interment.


The present disclosure relates to proteases having an amino acid sequence with at least about 70% sequence identity to the amino acid sequence given in SEQ ID NO:2, over the entire length thereof, and comprising an amino acid substitution at at least one of the positions P9, Q62, D101, N130, G166, N187, 5216, N238 or Q271, based in each case on the numbering according to SEQ ID NO:2. The present disclosure also relates to the production and use thereof. Such proteases exhibit very good stability, in particular storage stability, while at the same time having a good cleaning performance.

Proteases are among the industrially most significant enzymes of all. In the context of washing and cleaning agents, proteases are the longest established enzymes that are contained in virtually all modern, high-performance washing and cleaning agents. They cause the breakdown of protein-containing stains on the item to be cleaned. Of these proteases, subtilisin-type proteases (subtilases, subtilopeptidases, EC 220.127.116.11) are particularly significant, which proteases are serine proteases owing to the catalytically active amino acids. Said proteases act as non-specific endopeptidases and hydrolyze any acid amide bonds that are within peptides or proteins. Their pH optimum is usually in the highly alkaline range. An overview of this family is found, for example, in the article "Subtilases: Subtilisin-like Proteases" by R. Siezen, pages 75-95 in "Subtilisin enzymes", published by R. Bott and C. Betzel, New York, 1996. Subtilases are formed naturally by microorganisms. Of these, subtilisins that are formed by and secreted from Bacillus species should be mentioned in particular as the most significant group within the subtilases.
Examples of the subtilisin-type proteases that are preferably used in washing and cleaning agents are the subtilisins BPN′ and Carlsberg, protease PB92, subtilisins 147 and 309, protease from Bacillus lentus, in particular from Bacillus lentus DSM 5483, subtilisin DY, the enzymes thermitase, proteinase K and proteases TW3 and TW7, which belong to the subtilases but no longer to the subtilisins in the narrower sense, and variants of the mentioned proteases which have an altered amino-acid sequence by comparison with the starting protease. Proteases are altered, selectively or randomly, by methods known from the prior art, and are thereby optimized for use in washing and cleaning agents, for example. These methods include point, deletion or insertion mutagenesis, or fusion with other proteins or protein parts. Therefore, variants that are appropriately optimized are known for most of the proteases known from the prior art.
The European patent application EP 2 016 175 A1 discloses a protease from Bacillus pumilus provided for washing and cleaning agents, for example. In general, only selected proteases are at all suitable for use in liquid surfactant-containing preparations. In preparations of this kind, many proteases do not demonstrate sufficient catalytic performance or stability. In particular when used in washing agents which are usually purchased by the consumer in such an amount that several weeks or months may pass until the washing agent is finally consumed (i.e. the washing agents need to be stored by the consumer for weeks or months), many proteases demonstrate instability, which in turn leads to insufficient catalytic activity during the washing process. In phosphonate-containing liquid surfactant preparations, this problem is even more serious, for example due to the complex-forming properties of the phosphonates or due to disadvantageous interactions between the phosphonate and the protease.
As a result, protease- and surfactant-containing liquid formulations from the prior art have the disadvantage that, after storing, said formulations often do not have satisfactory proteolytic activity and therefore do not demonstrate optimal cleaning performance on protease-sensitive stains.

Proteases with improved enzyme stability in detergents


A sensor, suitable for being secured to a wheel bearing of a motor vehicle and serving to measure the rotational speed of the wheel, has a securing ring, a sensor block, at least one electrical line, at least one connector and at least one retaining bridge. The sensor block is electrically connected to the connector by means of the electrical line, and is connected to the securing ring at least by means of a plastic extrusion coating. A retaining bridge is integrally formed on the plastic extrusion coating and carries the connector until the sensor is installed at the location of its final intended position.

The invention relates to a sensor, in particular to a sensor which is secured to a wheel bearing of a motor vehicle and serves to measure the rotational speed, having a securing ring, a sensor block, at least one electrical line, at least one connector and at least one retaining bridge, with the sensor block being electrically connected to the connector by means of the electrical line, and the sensor block being connected to the securing ring at least by means of a plastic extrusion coating.
Sensors of the type mentioned in the introduction are used, for example, in motor vehicles for detecting the rotational speed of a wheel. Up until the sensor is installed at the location of its final intended position, that is to say on the wheel bearing of a motor vehicle for example, the connector has to be mounted in such a way that neither it nor the electrical line leading to it are damaged in any way. To this end, a transportation ring which securely holds the connector is fitted to the securing ring of the sensor in accordance with the prior art. When the sensor is installed at the location of its final intended position, the connector is removed from the transportation ring and is connected to the downstream electronics. The transportation ring is then removed from the securing ring and generally disposed of. This method of securing the connector to the sensor before said sensor is installed at the location of its final intended position is very complicated and expensive. Removal of the transportation ring from the sensor when said sensor is installed generates additional expenditure and the material of the transportation ring is lost.


A device for cleaning a bore of a firearm. One or more bore-cleaning bodies may include a core and a fabric cover, and a central member used to compress the core longitudinally and expand it radially to apply radial force pressing the fabric cover against the interior bore surface. A small-bore version may include flexible portions to be able to negotiate a breech mechanism of a repeating small arm.

The present invention is related to firearms, and particularly to apparatus for cleaning a bore of a firearm, either a cannon with a bore diameter of as much as 205 millimeters or a firearm with a smaller bore, including a shotgun or a rifle with a bore as small as .22 caliber.
Discharging firearms results in residue from the combustion of propellant and residue from wadding and the parts of a projectile that come into frictional contact with the interior surfaces of a gun tube. Cleaning a gun bore is periodically necessary to permit inspection, so that small cracks might be discovered before they can become dangerously enlarged. Cleaning is also necessary to avoid corrosion resulting from chemical products of combustion of a propellant, and to remove particulate matter left behind from friction of a projectile within the gun tube, particularly since some projectiles may leave behind particles of materials which might be dangerous or carcinogenic to personnel.
Currently the military is using a device similar in shape to a plumber's plunger to clean bores of guns. The same device in different sizes is used for several gun calibers, but this device does a poor job of cleaning the barrels of artillery guns. It requires many passes and up to six hours to clean a cannon barrel using this device.
In current cleaning methodologies, the cleaning process starts by inserting the cleaning device into the muzzle of the barrel and forcing the dislodged material towards the breech of the barrel. This in turn dictates that the residue must be blown out of the bore to complete the cleaning operation and in some cases such as cleaning a tank gun bore, residue thus can become airborne in a quite confined space. The residue then must be removed from that confined space, subjecting the armorer/technician to materials such as lead, carbon and in some cases depleted uranium particulates. Many such substances included in gun bore residues are known to have adverse affects on the human body.


Methods and systems are disclosed that enable the leveraging of financial instrument research at an individual financial instrument level but across multiple classifications of financial instruments to efficiently build an investment portfolio for an investor based on a desired portfolio objective through a plurality of graphical user interfaces (GUIs).

One of the more time-consuming and challenging tasks for financial advisors is the task of building investment portfolios for their customers such that the portfolio is populated with a diversified set of investment products that align with the investor's goals.
Many research analysts are employed within the financial services industries to analyze investment products and assess their value.
Exemplary embodiments of the present invention are directed toward the design of a method and system such that financial advisors are able to efficiently leverage such financial research when building investment portfolios for their customers. Associations between individual financial instruments and any of a plurality of portfolio objectives can be used by the exemplary systems and methods disclosed herein to automatically populate investment portfolios for investors with particular financial instruments based on a desired portfolio objective for an investor. Graphical user interfaces (GUIs) that are segmented by different classification groups of financial instruments can then be used to guide a user through the portfolio to ensure that the investor's portfolio meets desired diversification criteria and other goals of the investor.
These and other features and advantages of the present invention will be apparent to those having ordinary skill in the art upon a review of the disclosure herein.

Method and system for building an investment portfolio