Processes for producing flavorful and aromatic compounds from flue-cured tobacco material are provided. The processes involve providing a tobacco suspension comprising finely ground flue-cured tobacco material in intimate contact with ammonia, and subjecting the tobacco suspension to heat treatment for a time and under conditions sufficient to generate a flavorful and aromatic composition. The composition can be applied to smoking articles such as cigarettes to improve the flavor and aroma character thereof.

The present invention relates to smoking articles such as cigarettes, and in particular to processes for providing a flavorful and aromatic composition for tobaccos.
Popular smoking articles, such as cigarettes, have a substantially rod shaped structure and include a charge of smokable material such as strands or shreds of tobacco (e.g., cut filler) surrounded by a paper wrapper thereby providing a so-called xe2x80x9ctobacco rod.xe2x80x9d Numerous popular cigarettes have cylindrical filter elements aligned in an end-to-end relationship with the tobacco rod. Typically, filter elements are constructed from fibrous materials such as cellulose acetate, have a circumscribing plug wrap, and are attached to the tobacco rod using tipping material.
Many types of smoking products and improved smoking articles have been proposed through the years as improvements upon, or as alternatives to, the popular smoking articles. Recently, U.S. Pat. No. 4,708,151 to Shelar; U.S. Pat. No. 4,714,082 to Baneijee et al.; U.S. Pat. No. 4,756,318 to Clearman et al.; and U.S. Pat. No. 4,793,365 to Sensabaugh, Jr. et al.; and European Patent Publication Nos. 212,234 and 277,519 propose cigarettes and pipes which comprise a fuel element, an aerosol generating means physically separate from the fuel element, and a separate mouth-end piece. Such types of smoking articles provide natural tobacco flavors to the smoker thereof by heating, rather than burning, tobacco in various forms.
Generally, natural tobacco flavors and aromas are important for the taste, aroma, and acceptance of smoking products, including substitute smoking materials. Thus, the search for natural tobacco flavor additives or flavor substances is a continuing task.
To improve the flavor and aroma in smoking articles, various natural extracts prepared, e.g., from tobacco, have been included in smoking articles. For example, U.S. Patent No. 3,424,171 describes a process for the production of a non-tobacco smokable product having a tobacco taste. Tobacco is subjected to a moderate (i.e. below scorching) heat treatment, i.e., at from about 175xc2x0 C. to 200xc2x0 C. (350xc2x0 to 400xc2x0 F.), to drive off aromatic components. These components are trapped on adsorbent charcoal, and removed from the charcoal by solvent extraction.
Similarly, U.S. Pat. No. 4,150,677 describes a process for the treatment of tobacco which comprises the steps of: (1) contacting tobacco which contains relatively high quantities of desirable flavorants with a stream of non-reactive gas, under conditions whereby the tobacco is heated in a temperature range from about 140xc2x0 to 180xc2x0 C.; (2) condensing the volatile constituents of the resulting gaseous stream; and (3) collecting said condensate. The condensate may be used subsequently to flavor a smoking material in order to enhance the organoleptic qualities of its smoke.
British Patent No. 1,383,029 describes a method of obtaining tobacco aroma substances which comprises an extraction treatment wherein the components of the tobacco that are soluble in a suitable solvent are extracted and the residue obtained after removing the solvent is subjected to heat treatment at a temperature from 30xc2x0 to 260xc2x0 C.
U.S. Pat. No. 5,038,802 to White et al. and U.S. Pat. No. 5,016,654 to Bemasek et al. disclose extraction processes which heat tobacco and then pass an inert atmosphere through the heating chamber to collect volatiles from the tobacco. The volatiles are then fractionated in downstream operations, which include liquid sorbents, cold temperature traps, and filters.
U.S. Pat. No. 5,235,992 to Sensabaugh proposes a process that involves heating tobacco (e.g., in a flowing gas stream) during a first staged heating to a first xe2x80x9ctoastingxe2x80x9d temperature to drive off volatile materials, increasing the toasting temperature during a second staged heating, and separately collecting, as flavor substances, at least portions of the volatile materials driven off at the first and second toasting temperatures.
U.S. Pat. No. 5,121,757 to White et al. proposes a process for altering the chemical nature of a tobacco extract, in which tobacco material is extracted with a chemical solvent, the extract is contacted with an ammonia compound, and the ammonia-treated extract is subjected to heat treatment in a pressure-controlled environment (e.g., in a Parr bomb).
Other processes for producing and using tobacco extracts, aroma oils and concentrates are proposed in U.S. Pat. No. 3,136,321 to Davis; U.S. Pat. No. 3,316,919 to Green; U.S. Pat. No. 3,424,171 to Rooker; U.S. Pat. No. 4,421,126 to Gellatly and U.S. Pat. No. 4,506,682 to Mueller and European Patent Publication No. 338,831 to Clapp et al.
It has also been proposed to treat tobacco to improve the flavorful and aromatic characteristics in situ. The treated tobacco with improved flavor and aroma is used in making smoking articles such as cigarettes. For example, in the method disclosed in U.S. Pat. No. 4,607,646, cured tobacco, in particular bright tobacco is subjected to heat treatment in the continuing presence of ammonia for a period of xc2xd to 24 hours at a temperature of 80xc2x0 C. to 150xc2x0 C. in a closed system. The resultant tobacco is described as having Burley-like flavor characters.
U.S. Pat. No. 4,677,994 proposes a process of forming favorable flavor compounds in a moisturized tobacco. Tobacco lamina applied with ammonium hydroxide is treated in pressurized steam and then discharged into a zone of lower pressure to expand the tobacco. Improvements in flavor and reduced irritation are observed in the resultant tobacco.
In addition, others have proposed to react non-tobacco materials to produce flavorful and aromatic compounds for use in smoking articles. For example, U.S. Pat. No. 5,413,122 to Shu issued on May 9, 1995 discloses making a flavorful and aromatic composition from xcex2-hydroxy amino acids by contacting the amino acids with a liquid having an aqueous character followed by heat treatment in an enclosed environment to provide an aqueous solution of volatile pyrazine flavorants. The ratio of liquid to amino acid is 4:1 to 40:1. The resulting aqueous extract containing flavorful pyrazines is then applied to smoking materials to provide flavor and aroma in the smoking articles.
U.S. Pat. No. 3,478,015 discloses heating an amino acid and a sugar in the presence of a polyhydric alcohol and using the reaction product as a flavoring material.
U.S. Pat. No. 3,920,026 describes reacting the amino acid valine with a sugar, other hydroxycarbonyl compound, or dicarbonyl compound under heat treatment in a solvent such as glycerol or propylene glycol and at a temperature of about 100xc2x0 C. to about 200xc2x0 C. for about 0.5 to 5 hours. Optionally, a catalyst such as a flavanoid or hydroxyacid is included in the reaction. The reaction products can be used as flavorants in tobacco compositions.
U.S. Pat. No. 4,306,577 discloses the production of flavorants for smoking compositions by reacting reducing sugars and selected amino acids in the presence of ammonium hydroxide and optionally in the presence of an aldehyde in an essentially solvent-free system at a temperature range of 90xc2x0 C. to 115xc2x0 C. The selected amino acids are those that have at least two nitrogens such as glutamine, asparagine, lysine, and arginine.
Similarly, U.S. Pat. No. Re. 32,095 discloses reacting a reducing sugar with a source of ammonia in the presence of a trace amount of certain amino acids at a temperature in the range of about 90xc2x0 C. to about 115xc2x0 C. for about 5 to 15 minutes. The trace amino acids include aspartic acid, glutamic acid, asparagine, and glutamine. The weight ratio of sugar to amino acid is in the range of 200-300:1, and the weight ratio of sugar to ammonia source is about 5-15:1.
While these processes have produced flavor substances acceptable for use in many smoking articles, they have not been suitable for some smoking articles, or have required costly or time consuming steps such as forming a tobacco extract prior to the obtaining of the desired compounds, or have subjected tobacco materials to some extreme conditions before incorporating them into smoking articles. Additionally, many of these processes have necessarily required expensive or inabundant starting materials.
The present invention generally relates to a process for the production of natural tobacco flavor substances useful in tobacco smoking products as flavorants, and in tobacco substitute materials as a source of tobacco smoke flavor and/or aroma. The process of this invention produces suspensions having a complex mixture of volatile, semi-volatile, and non-volatile aroma/flavor components that are products of the Maillard reactions.
In accordance with a first aspect of this invention, flue-cured tobacco material is contacted with an aqueous liquid to form a tobacco suspension. Ammonia is provided in the tobacco suspension under conditions such that the ammonia is in intimate contact with the flue-cured tobacco material in the suspension. The tobacco suspension is subject to heat treatment for a time and under conditions sufficient to provide a flavorful and aromatic composition, which can be applied to tobacco material as a casing or top dressing ingredient.
In a preferred embodiment, tobacco in the form of finely divided particles (finely ground tobacco material) is produced from flue-cured tobacco material and is mixed with an aqueous liquid and ammonia to produce the tobacco suspension. This suspension is subjected to heat treatment in a closed pressure controlled environment (e.g., a Parr bomb) under conditions sufficient to produce the flavorful and aromatic composition. In general, the treatment temperature and time are selected such that the tobacco suspension is exposed to a temperature sufficiently high and for a period of time sufficiently long so as to provide an increase in aroma/flavor compounds. However, it is preferable that the tobacco suspension not be exposed to such a high temperature for a sufficiently long period of time so as to provide an aroma/flavor which exhibits a burnt or tarry aroma/flavor. Thus, for the purposes of this invention, it is convenient to refer to the heat treatment, or the moderately high temperature treatment, of a tobacco suspension.
The tobacco suspension comprising flue-cured tobacco material and ammonia should have sufficient aqueous liquid such that a liquid phase is present in the suspension. Typically the tobacco suspension can include solids in an amount of about 80% by weight or less. More preferably, the suspension contains less than 75% by weight, even more preferably less than 50% by weight solids, and most preferably contains between 10% and 25% by weight solids. For the purposes of this invention, a tobacco suspension can include tobacco material in a dust or powder form, together with ammonia, and the aqueous liquid can further include additives including amino acids, amino acid analogs or amino acid sources or other nitrogen sources, and/or sugar (or sugar sources). Preferred amino acids include threonine, serine, leucine, isolecine, and valine.
The ammonia can be provided in the suspension via anhydrous ammonia in a gaseous form (e.g., ammonia gas) or via aqueous ammonia (e.g., ammonia hydroxide). Preferably, the ammonia is aqueous ammonium hydroxide, i.e., by dissolving ammonia gas or concentrated ammonium hydroxide in the aqueous liquid.
Typically, the tobacco suspension is subjected to heat treatment at a temperature significantly above about 95xc2x0 C. in a pressure controlled and generally inert environment. In particular, it has been found that the amount of aromatic flavorants generated in the present invention is significantly increased when the temperature of the heat treatment is increased to above 95xc2x0 C. Preferably the heat treatment is conducted at a temperature of above 100xc2x0 C., more preferably at least about 120xc2x0 C., and most preferably at least about 145xc2x0 C. It has been discovered that the pyrazine yield is particularly high when the temperature for heat treatment is 120xc2x0 C. or greater.
The heat treatment step of the present invention can be conducted in the presence of inert gas or ambient air, and additional oxygen or an equivalent oxidizing agent are not required. In general, the pressure experienced by the tobacco suspension is greater than ambient (i.e., atmospheric) pressure. Typical pressures experienced by the tobacco suspension during the process of the present invention in an enclosed vessel range from about 10 psig to about 1,000 psig, normally from about 20 psig to about 500 psig, preferably about 20 psig to about 100 psig.
The resultant flavorful and aromatic compositions are useful as casing or top dressing components for tobacco laminae and cut filler, as well as for other smokable materials. Alternatively, such flavorful and aromatic compositions are useful in those types of smoking articles described in U.S. Pat. No. 4,708,151 to Shelar; U.S. Pat. No. 4,714,082 to Banerjee et al.; U.S. Pat. No. 4,756,318 to Clearman et al.; and U.S. Pat. No. 4,793,365 to Sensabaugh; as well as European Patent Publication Nos. 212,234 and 277,519.
The flavorful and aromatic compositions are also useful as cigarette filter additives. For example, the flavorful and aromatic compositions can be incorporated into low density polyethylenes and formed into strands, and then incorporated into cigarette filters as described in U.S. Pat. No. 4,281,671 to Byrne et al. and U.S. Pat. No. 4,862,905 to Green, Jr. et al. The flavorful and aromatic compositions are also useful as cigarette wrapper additives; or as additives to the inner regions of cigarette packages (e.g. within a paper/foil laminate of a cigarette package or within a low density polyethylene film which is placed within a cigarette package) in order to provide a desirable cigarette aroma and xe2x80x9cpack aroma.xe2x80x9d
Flavor compounds produced by the methods of the present invention have organoleptic qualities and volatile content qualities that are comparable to those compounds produced by solvent extraction of natural compounds and heat treatments thereof, and those compounds generated based on conventional cooked casing formulations.
In contrast to other cooked-casing formulations which typically require use of substantial amounts of reducing sugars along with a nitrogen source, the method of the present invention does not require reducing sugars in the tobacco suspension. Nevertheless, the heat treatment of the tobacco suspension generates flavorful and aromatic compounds in an amount and quality comparable to those produced in conventional formulations.
Additionally, it has been found that tobacco materials formerly discarded as waste products of the manufacturing process may be used as starting materials in the process of the present invention to yield flavorful aromatic substances that are comparative in concentration of desirable organoleptic components to conventional tobaccos. Tobacco dust represents a significant portion of tobacco material lost during the manufacture of cigarettes. Thus, the present invention provides a simple, inexpensive and efficient method for producing aroma and flavor components for the manufacture of smoking articles and the like while also reducing waste in the manufacturing process.
These and other advantages of the present invention are more completely illustrated the following detailed description of the preferred embodiments of the invention and the accompanying examples.
In accordance with the present invention, a tobacco suspension comprising flue-cured tobacco material in intimate contact with ammonia is subjected to heat treatment for a time and under conditions sufficient to generate a flavorful and aromatic composition. The composition can be applied to smoking articles such as cigarettes to improve the flavor and aroma character thereof.
Flue-cured tobacco is generally known in the art and refers to a class of tobaccos grown, harvested and processed by particular methods known in the art. See generally Browne, The Design of Cigarettes. Bright tobacco and Virginia tobacco are commonly used flue-cured tobaccos in the U.S. Typically, flue-cured tobaccos are processed by xe2x80x9cflue-curingxe2x80x9d or similar methods, and have a high sugar content while their nitrogen content is relatively low. It is to be understood that, as used herein, the term xe2x80x9cflue-cured tobaccoxe2x80x9d is inclusive and includes tobaccos that are not strictly classified as flue-cured tobacco but nevertheless have chemistry profiles, in particular, sugar and nitrogen content profiles, similar to those of typical flue-cured tobacco. Normally, the xe2x80x9cflue-cured tobaccoxe2x80x9d used in the present invention has a reducing sugars (calculated as dextrose) content of at least about 2%, preferably at least about 5%, more preferably at least about 10% by weight based on the total dry tobacco weight. Advantageously, the total reducing sugars content (calculated as dextrose) is 15% or greater based on the total dry weight of tobacco.
Other types of tobacco can also be included, in addition to xe2x80x9cflue-cured tobacco,xe2x80x9d in the tobacco suspension of the present invention. Examples of such other tobacco types include, but are not limited to, air-cured tobacco including Burley and Maryland tobaccos, sun-cured tobacco such as Oriental tobacco, and Turkish, Latakia, as well as the rare or specialty tobaccos, or blends thereof. Unaged, uncured, mature or immature tobaccos, or blends thereof may also be employed. However, advantageously at least about 20% by weight of the total tobacco content is flue cured tobacco; preferably at least about 50%, more preferably at least about 70%, and most preferably at least about 80% of the total tobacco is flue cured tobacco. As flue-cured tobacco generates the most desirable results in the process of the invention, it is advantageous that a substantial portion, e.g., at least 90%, of the total tobacco content is flue-cured tobacco. Preferably, 100% of the total tobacco content is flue-cured tobacco.
The tobacco material in the tobacco suspension can be in various forms, e.g., leaves, stems, strips, cut fillers, shreds, etc. Tobacco waste materials such as fines, dust, scrap, stem, and stalk can be employed. In one preferred embodiment of the present invention, the tobacco material comprises a cigarette manufacturing by-product known to the skilled practitioner as xe2x80x9ctobacco dust.xe2x80x9d
Preferably, the tobacco material is in the form of finely divided particles. The aforementioned tobacco material can be subjected to various means to reduce its size, such as grinding, such that the resulting tobacco material is in finely ground tobacco material dust or powder. Various grinding techniques will be apparent to one skilled in the art, and may include the use of, e.g., ball mills or hammer mills. The grinding may also be carried out under vibrating or agitating conditions, the selection of said conditions being within the skill of one in the art. As used herein, the term xe2x80x9cfinely tobacco ground materialxe2x80x9d refers to tobacco materials composed of particles that are less than 10 mesh, preferably less than 20 mesh, and most preferably are less than 40 mesh (standard sieve size). That is, the fine particles most preferably can pass a 40 mesh (Tyler) screen. Alternatively, the tobacco material may already be in dust form such that additional grinding is not necessary (i.e., the starting tobacco material is already finely divided).
The tobacco suspension typically is provided by contacting tobacco material including flue-cured tobacco material with ammonia and sufficient liquid such that a liquid phase is present in the suspension. The liquid is primarily of an aqueous character and contains primarily of water. Ammonia can be introduced into the tobacco suspension in various forms. Ammonia can be introduced into the aqueous liquid prior to or after the tobacco material is contacted with the liquid. For example, ammonia in a gaseous form can be conveniently injected into or bubbled through the aqueous liquid or suspension. Alternatively, a concentrated ammonium hydroxide solution can be diluted into the aqueous liquid or suspension. Typically, the ammonia hydroxide concentration in the tobacco suspension is at least about 10 mM, preferably at least about 50 MM, more preferably at least about 0.1 M, and most preferably at least about 0.5 M. Normally, the ammonium hydroxide concentration in the tobacco suspension is not greater than 5 M, although a higher concentration may also be effective. Advantageously the ammonia hydroxide concentration is from about 0.5 M to about 2 M.
The aqueous liquid normally contains greater than about 90 weight percent water, and can be essentially pure water in certain circumstances. For example, a liquid having an aqueous character can be distilled water, tap water, or the like. However, a liquid having an aqueous character can include water having substances such as pH buffers, organic and inorganic acids, bases and salts, or surfactants incorporated therein, or minor amounts of one or more organic solvents (e.g., various alcohols, polyols or humectants such as glycerin or polypropylene glycol).
In the tobacco suspension, the tobacco content can vary. Typically, the content of flue-cured tobacco may be at least about 5 percent of the total suspension by weight, preferably at least about 10 percent by weight, and more preferably at least about 25 percent by weight. The tobacco suspension can have 80% by weight or less solids, more preferably less than about 50% by weight solids.
The tobacco suspension can also include an exogenous reducing sugar or reducing sugar source. The tobacco suspension may have a reducing sugar content of from 0% by weight to up to about 15%, although a higher concentration may also be used. As is known in the art, tobacco materials including flue-cured tobaccos typically contain a certain amount of reducing sugars or compounds such as disaccharides and polysaccharides which can release reducing sugars therefrom. As used herein, the term xe2x80x9cexogenous reducing sugar or reducing sugar sourcexe2x80x9d means reducing sugar or reducing sugar source that is not contained in or derived from the tobacco materials in the tobacco suspension, i.e., they are exogenous to the tobacco materials.
Suitable reducing sugars that can be used in the invention include, but are not limited to, glucose, fructose, sucrose, mannose, galactose, rhanmose, and mixtures thereof The reducing sugar can be in a pure form or in unrefined form, e.g., high fructose corn syrup (HFCS) which has a high content of fructose. Many derivatives of reducing sugars can also be used, e.g., phosphate-substituted reducing sugars (e.g., glucose-6-phosphate, fructose-6-phosphate, and fructose-1,6-diphosphate). Reducing sugars can also be provided in the form of precursors that can readily release reducing sugars under the reaction conditions employed in the method of this invention. Examples of suitable precursors can include disaccharides and polysacchrides, and derivatives thereof. In such cases, reducing sugars can be generated by the hydrolysis of disaccharides or polysaccharides. In a preferred embodiment of the invention, a high fructose corn syrup (HFCS) having at least about 30% by weight of fructose is used as the reducing sugar component. For example, a high fructose corn syrup having about 42% by weight of fructose is commercially available from Corn Products International, Bedford Park, Ill.
Additionally, although not required, the tobacco suspension can optionally include one or more exogenous amino acids, amino acid source, or amino acid analog. Again, the term xe2x80x9cexogenousxe2x80x9d is used herein to mean additional amino acids or amino acid sources exogenous to the tobacco materials in the tobacco suspension. Threonine, serine, leucine, isoleucine, and valine are the preferred amino acids.
If desired, flavoring agents, e.g., cocoa, licorice, St. John""s bread, spices, herbs, and the like can also be added to the tobacco suspension. Base materials, particularly ammonium salts of inorganic acids such as ammonium orthophosphate, ammonium dihydrogen orthophosphate, diammonium monohydrogen orthophosphate, and the like may also be included.
The tobacco suspension is subjected to a heat treatment such as generally described in U.S. Pat. No. 5,060,669 to White et al., the disclosure of which is incorporated herein by reference in its entirety. The heat treatment can be conducted at a temperature of at least about 95xc2x0 C., preferably at least about 110xc2x0 C., more preferably at least about 135xc2x0 C., and most preferably at least about 145xc2x0 C. Advantageously, the heat treatment can be conducted at a temperature of 155xc2x0 C. or greater. However, it is desirable to subject the tobacco suspension to a temperature below about 250xc2x0 C., more desirably below about 200xc2x0 C., in order to avoid an undesirable formation of components which are deleterious to the taste characteristics of the tobacco composition.
The moderately high temperature treatment is performed in a pressure controlled environment. Such an environment is provided by enclosing the tobacco suspension in an air sealed vessel or chamber. Typically, a pressure controlled environment is provided using a pressure vessel or chamber which is capable of withstanding relatively high pressures. Such vessels or chambers (i) provide enclosure or concealment of the tobacco suspension such that ammonia is contained and in intimate contact with the tobacco materials in the suspension during the heat treatment, (ii) provide enclosure of the tobacco suspension such that volatile flavor components generated during the heat treatment are not lost or do not otherwise escape during the moderately high temperature treatment step, and (iii) provide for treatment of the tobacco suspension at a temperature above about 95xc2x0 C. Preferred pressure vessels are equipped with an external heating source. Examples of vessels which provide a pressure controlled environment include a high pressure autoclave from Berghof/America Inc. of Concord, Calif., and Parr Reactor Model Nos. 4522 and 4552 available from The Parr Instrument Co. and described in U.S. Pat. No. 4,882,128 to Hukvari et al. Operation of such exemplary vessels will be apparent to the skilled artisan. Typical pressures experienced by the tobacco suspension during the process of the present invention in such vessels range from about 10 psig to about 1,000 psig, normally from about 20 psig to about 500 psig, preferably about 20 psig to about 100 psig.
The amount of time that the tobacco suspension is subjected to the moderately high temperature treatment can vary. Normally, the time period is sufficient to heat an entire tobacco suspension at the desired temperature for a period of at least about 10 minutes, preferably at least about 20 minutes. Typically, when the heat treatment is conducted at a higher temperature, less time is required for the heat treatment. It is desirable to control the time/temperature profile of tobacco suspensions subjected to heat treatment so that each tobacco suspension is not subjected to a particularly high temperature for a lengthy period of time. Although a longer time period may be used for the heat treatment, typically, the time period is less than about 3 hours, preferably no greater than about 1 hour. Some minor degree of experimentation may be required to determine the optimal time period at a particular heat treatment temperature, this being well within the capability of one skilled in the art once apprised of the present disclosure.
It is highly desirable to employ a pressure vessel design or a vessel equipped with an agitation mechanism such that the tobacco suspension experiences a relatively uniform temperature throughout the treatment period. In particular, it is highly desirable for the entire tobacco suspension to be heated uniformly throughout as much as possible at the maximum temperature to which the tobacco suspension is subjected.
Conditions provided during the process of the present invention most desirably are such that certain components of the tobacco suspension (e.g., naturally occurring sugars and ammonium) undergo the Maillard Reactions or xe2x80x9cbrowning reactionsxe2x80x9d to form flavorful and aromatic compounds including pyrazines. The Maillard Reactions are reactions between (i) ammonium or the amino substituent of amino acids, peptides, proteins or other nitrogen-containing compounds, and (ii) the carbonyl group of a sugar in the reducing form or other carboxyl-containing compounds which are endogenous or added to the tobacco suspension. Such reactions result in a significant darkening of the tobacco suspension, typically to an extremely dark brown color. See e.g., Maillard, Ana Chim., Vol. 9, pp. 5 and 258 (1916); Hodge, J. Agric. Food Chem., Vol. 1, p. 928 (1953); Nursten, Food Chem., Vol. 6, p. 263 (1981) and Waller et al, ACS Symp. Ser. (1983).
The resultant composition after the heat treatment contains flavorful and aromatic compounds and is useful as flavorant material in the manufacture of smoking articles. When the tobacco suspension subjected to heat treatment contains tobacco materials that are in strips, stems, leaves, and the like and are not in finely ground particle forms, the heat treated tobacco suspension can be subjected to any various size reduction processes to reduce the tobacco materials to fine particles and to form a slurry. The resultant slurry can be incorporated into smoking articles during the manufacturing .process as a top dressing or casing ingredient, or in any convenient mode selected by the manufacturer. Similarly, when the tobacco materials in the tobacco suspension are in a fine particle form, the slurry formed after the heat treatment can be applied directly to and/or incorporated directly into smoking articles in the form of, e.g., casing or top dressing material. Alternatively, the solid materials can be separated from the aqueous liquid by any suitable means and the liquid component of the treated tobacco suspension can be applied, e.g., as casing or top dressing ingredients, to tobacco material such as tobacco lamina or cut filler. The tobacco material can be natural tobacco, or prepared from reconstituted or substituted tobaccos.
The amount of the treated tobacco suspension employed per cigarette or smoking article can vary. For example, in a typical cigarette having about 0.6 to about 1 g per rod of smokable material, about 0.1 to 10% by weight, preferably about 0.5 to 6% by weight, more preferably about 1 to 2.5% by weight of the heat treated suspension based on the total weight of the smokable material in the smoking article, either in the form of slurry, or liquid or solids, can be used as a top dressing or casing.
Moreover, the treated tobacco suspension may be used as a filter flavor material for a cigarette. The suspension may be used to provide flavor/aroma to any of the forms of material that are used in the manufacture of tobacco products such as cigars, cigarettes, smoking tobacco or snuffs.
The present invention is more fully illustrated by the following examples, which are set forth to illustrate the present invention and are not to be construed as limiting thereof In the following examples, mg means milligram, xcexcg means micrograms, g means grams, L means liters, mL means milliliters, min means minutes, and mm means millimeters.


The invention concerns a method for purifying biological macromolecules, e.g. nucleic acids or proteins, from starting materials, in which the macromolecules, contained in a biological solution, are purified on a chromatographic material, and in which endotoxins are partially or completely removed with the aid of a nonionic surfactant, which is characterized in that the surfactant and the biological solution are brought into contact immediately before or during the purification of the macromolecules on the chromatographic material.

The invention concerns a method for purifying biological macromolecules, e.g. nucleic acids or proteins, from starting materials, in which the macromolecules, contained in a biological solution, are purified on a chromatographic material, and in which endotoxins are partially or completely removed with the aid of a nonionic surfactant. The invention is furthermore based on a chromatographic column for performing this method which contains a chromatographic material enclosed by closure filters.
Gene therapy is increasingly being used for the treatment of certain diseases. For this purpose, preparations which contain macromolecules such as nucleic acids or proteins as their active ingredients are obtained from biological starting material, e.g. from bacteria modified by genetic engineering. The preparations are then introduced into the human body.
It is essential for the success of gene therapy that the preparation be free of toxic substances. Since the preparations in question are usually isolated from bacteria such as the Gram-negative enterobacterium E. coli, and these bacteria contain as cell-wall constituents lipopolysaccharides (LPSs) that are also referred to as endotoxins, the removal of such endotoxins is very important. The reason is that intravenously administered preparations can cause fever, inflammatory reactions, or irreversible shock if they contain even small concentrations of endotoxins.
Various methods are known for removing the endotoxins. In a number of methods, this is done by using nonionic surfactants, for example the Triton X-114(copyright) surfactant of the Rohm and Haas company, specifically in conjunction with the method utilized for purifying and isolating the macromolecules. With these methods, the biological starting material containing the macromolecules is digested using a common method. Cell digestion can be accomplished by so-called alkaline lysis, by the action of high temperatures (boiling lysis), by the action of mechanical forces (compression/expansion, French press), or by the action of enzymes or detergents that destroy the cell membrane. Cell debris is then removed from the resulting cell lysate by mechanical methods, for example filtration or centrifuging.
In a subsequent step, the resulting lysate (also called xe2x80x9ccleared lysatexe2x80x9d) is purified chromatographically. This is done by binding the macromolecules contained in the lysate to a chromatographic material having an anion exchange function. What is used in the existing art is a cartridge into which the chromatographic material is inserted. This can preferably be a porous or nonporous, inorganic or organic sorbent modified with an anion exchange function. A washing buffer is added in order to remove undesired substances. This is followed by elution of the macromolecules by adding an elution buffer. The eluted macromolecules are precipitated and are then available for further applications.
To remove the endotoxins, Aida et al. (Journal of Immunological Methods, 132 (1990), 191-195) and Manthorpe et al. (Human Gene Therapy 4 (1993), 419-431) recommend adding Triton X-114(copyright) surfactant to the solution with the macromolecules (once they have been chromatographically isolated and purified), and incubating the solution. The endotoxins bound to the surfactant are then removed by phase separation via centrifuging. A phase separation of this kind can be achieved, however, only if temperature conditions are strictly observed, temperature control of the centrifuge that is used being particularly complex. Repeated incubation at temperatures of 50xc2x0 C. or 40xc2x0 C. can cause irreversible damage to sensitive molecules.
EP-A-0 308 239 proposes removing endotoxin from an aqueous, purified, biologically usable, macromolecule-containing solution by adding a dialysable surfactant to the solution, and then bringing the solution into contact with a water-insoluble endotoxin sorbent in order to bind the endotoxins to the sorbent. The remaining liquid phase is then separated from the sorbent, and the surfactant is removed by dialysis. This yields a surfactant-free aqueous solution of the biological macromolecule, with a reduced concentration of endotoxins, which is usable for in vivo applications.
A similar method is evident from WO 97/29113. With this method the endotoxins are removed, after purification of the nucleic acids, in a further step using hydroxylapatite chromatography. In both cases, there is an increased outlay in terms of equipment, and the time required is considerable.
WO 95/21177 and WO 95/21179 propose, in addition to other methods for endotoxin removal, adding to the filtered or centrifuged lysate (cleared lysate) a buffer that contains, inter alia, 10% Triton X-100(copyright) or Triton X-114(copyright). The solution is preincubated for a long period at low temperatures before being passed on for chromatographic purification. This method has the same disadvantages as the method described above. In addition, with all the methods the removal of endotoxins requires an additional process step, which considerably lengthens and complicates the purification and isolation procedure. In the case of sensitive nucleic acid molecules, this can result in decreased yield.
It is the object of the invention to make available a method for producing biological macromolecules containing little or no endotoxin that can be performed easily, quickly, and thus economically, and is also reliably reproducible. A further object is to make available a chromatographic column for carrying out this method.
According to the present invention, this object is achieved in that the surfactant and the biological solution are brought into contact immediately before or during the purification of the macromolecules on the chromatographic material. The basic concept of the invention is thus to remove endotoxins from the macromolecule-containing biological solution by the fact that the endotoxins enter into interaction with surfactants simultaneously with and in the same place as the chromatographic purification of the biological macromolecule, and thus do not bind to the chromatographic material and consequently can be washed out of the chromatographic material; the washing-out operation can be assisted by the use of detergent-containing solutions. It has been found, surprisingly, that very effective depletion of endotoxins can hereby be achieved with no need for time-consuming incubation and extraction steps. Since endotoxin removal takes place simultaneously with the purification and isolation of the macromolecules on the chromatographic material, a definite economy in terms of time and effort is attained.
The term xe2x80x9csurfactantxe2x80x9d is also to be understood as a mixture of different surfactants. In this context, the surfactant should belong to the group of the polyethylene glycol ethers, and preferably should be Triton X-114(copyright).
It has proven to be particularly advantageous to supply the nonionic surfactant as a constituent of washing buffers that are used in any case on the chromatographic material. Alternatively or (better yet) in combination therewith, the chromatographic material, and/or a closure filter in a chromatographic column containing said material, should be impregnated with the surfactant. The surfactant should be present in the washing buffer and/or in the chromatographic material and/or in the closure filter at a concentration of 0.1to 10%.
With regard to the second portion of the object, provision is made according to the present invention for the closure filter and/or the chromatographic material itself to be equipped with a nonionic surfactant, for example Triton X-114(copyright).
A porous or nonporous, inorganic or organic sorbent, modified with anion exchange functions, can be used as the chromatographic material. Suitable closure filters are macroporous, sintered glass or a similar plastic, as well as compressed or interwoven synthetic mats made of polyamide, polyester, polypropylene, cellulose, or combinations of said materials. Preferably the closure filter and/or the chromatographic material is impregnated with the surfactant. The surfactant should be present at a concentration of 0.1 to 10%. The closure filter can vary greatly in thickness. The greater the thickness, the more surfactant it can bind for the endotoxin removal process. Advantageously, the thickness is between 1 and 15 mm.

Method for purifying biological marcromolecules, and chromatographic column for performing said method


A floor cleaning wipe comprising a water insoluble substrate which is impregnated with a floor cleaning composition.

The present invention relates to a floor cleaning wipe which comprises a water insoluble substrate which has been impregnated with a liquid floor cleaning composition.
The patent literature describes numerous wipes for both body cleaning and cleaning of hard surfaces but none describe the instant cleaning wipes which have improved cleaning characteristics in the minimization of streaking and residue, together with optimum mileage.
U.S. Pat. Nos. 5,756,612; 5,763,332; 5,908,707; 5,914,177; 5,980,922 and 6,168,852 teach cleaning compositions which are inverse emulsions.
U.S. Pat. Nos. 6,183,315 and 6,183,763 teach cleaning compositions containing a proton donating agent and having an acidic pH.
U.S. Pat. Nos. 5,863,663; 5,952,043; 6,063,746 and 6,121,165 teaches cleaning compositions which are emulsions.
A floor cleaning wipe for cleaning floors comprises a water insoluble substrate which is impregnated with a liquid cleaning composition containing an anionic surfactant, at least one nonionic surfactant, a short chain amphiphile, an inorganic magnesium salt, and water, wherein the liquid cleaning composition is not an emulsion and does not contain a zwitterionic surfactant, proteins, metallic salts, enzymes, amides, sodium hypochlorite, dimethicone, N-methyl-2-pyrrolidone, monoalkyl phosphate or silicon based sulfosuccinate.
The present invention relates to a floor cleaning wipe for hard surfaces which comprises approximately:
(a) 10 wt. % to 30 wt. % of a water insoluble substrate; and
(b) 70 wt. % to 90 wt. % of a liquid floor cleaning composition being impregnated in said water insoluble substrate, wherein said liquid cleaning composition comprises:
(i) 0.01 wt. % to 2 wt. %, more preferably 0.02 wt. % to 1.5 wt. % of an anionic surfactant;
(ii) 0.01% to 0.5% of an inorganic magnesium salt;
(iii) 0.01% to 0.5% of a short chain amphiphile;
(iv) 0.005 wt. % to 1 wt. % of preservative ingredients such as 1,3-dimethylol-5,5-dimethylhydantoin, 5-bromo-5-nitro-dioxane, iodopropynyl butyl carbamate and mixture thereof;
(v) 0.05% to 0.5% of a chelating agent such as sodium ethylenediamine-N,N-tetraacetate or sodium ethylenediamine-N,N-disuccinate
(vi) 0.01 to 0.5 wt. % of a perfume;
(vii) 0.05 wt. % to 4 wt. %, more preferably 0.75 wt. % to 3.0 wt. % of at least one ethoxylated nonionic surfactant; and
(viii) the balance being water, wherein the composition has a pH of about 5.5 to about 7, more preferably about 5.8 to about 7.0.
The anionic sulfonate surfactants which may be used in the cleaning compositions of this invention are water soluble and include the sodium, potassium, ammonium and ethanolammonium salts of linear C8-C16 alkyl benzene sulfonates; C10-C20 paraffin sulfonates, alpha olefin sulfonates containing about 10-24 carbon atoms and C8-C18 ethoxylated alkyl ether sulfates and mixtures thereof. The preferred anionic sulfonate surfactant is a C12-18 paraffin sulfonate.
The paraffin sulfonates may be monosulfonates or di-sulfonates and usually are mixtures thereof, obtained by sulfonating paraffins of 10 to 20 carbon atoms. Preferred paraffin sulfonates are those of C12-18 carbon atoms chains, and more preferably they are of C14-17 chains. Paraffin sulfonates that have the sulfonate group(s) distributed along the paraffin chain are described in U.S. Pat. Nos. 2,503,280; 2,507,088; 3,260,744; and 3,372,188; and also in German Patent 735,096. Such compounds may be made to specifications and desirably the content of paraffin sulfonates outside the C14-17 range will be minor and will be minimized, as will be any contents of di- or poly-sulfonates.
Examples of suitable other sulfonated anionic detergents are the well known higher alkyl mononuclear aromatic sulfonates, such as the higher alkylbenzene sulfonates containing 9 to 18 or preferably 9 to 16 carbon atoms in the higher alkyl group in a straight or branched chain, or C8-15 alkyl toluene sulfonates. A preferred alkylbenzene sulfonate is a linear alkylbenzene sulfonate having a higher content of 3-phenyl (or higher) isomers and a correspondingly lower content (well below 50%) of 2-phenyl (or lower) isomers, such as those sulfonates wherein the benzene ring is attached mostly at the 3 or higher (for example 4, 5, 6 or 7) position of the alkyl group and the content of the isomers in which the benzene ring is attached in the 2 or 1 position is correspondingly low. Preferred materials are set forth in U.S. Pat. No. 3,320,174, especially those in which the alkyls are of 10 to 13 carbon atoms.
The C8-18 ethoxylated alkyl ether sulfate surfactants have the structure
Rxe2x80x94(OCHCH2)nOSO3xe2x88x92M+
wherein n is about 1 to about 22 more preferably 1 to 3 and R is an alkyl group having about 8 to about 18 carbon atoms, more preferably 12 to 15 and natural cuts, for example, C12-14 or C12-16 and M is an ammonium cation or a metal cation, most preferably sodium.
The ethoxylated alkyl ether sulfate may be made by sulfating the condensation product of ethylene oxide and C8-10 alkanol, and neutralizing the resultant product. The ethoxylated alkyl ether sulfates differ from one another in the number of carbon atoms in the alcohols and in the number of moles of ethylene oxide reacted with one mole of such alcohol. Preferred ethoxylated alkyl ether polyethenoxy sulfates contain 12 to 15 carbon atoms in the alcohols and in the alkyl groups thereof, e.g., sodium myristyl (3 EO) sulfate.
Ethoxylated C8-18 alkylphenyl ether sulfates containing from 2 to 6 moles of ethylene oxide in the molecule are also suitable for use in the invention compositions. These detergents can be prepared by reacting an alkyl phenol with 2 to 6 moles of ethylene oxide and sulfating and neutralizing the resultant ethoxylated alkylphenol.
As used herein and in the appended claims the term xe2x80x9cperfumexe2x80x9d is used in its ordinary sense to refer to and include any non-water soluble fragrant substance or mixture of substances including natural (i.e., obtained by extraction of flower, herb, blossom or plant), artificial (i.e., mixture of natural oils or oil constituents) and synthetically produced substance) odoriferous substances. Typically, perfumes are complex mixtures of blends of various organic compounds such as alcohols, aldehydes, ethers, aromatic compounds and varying amounts of essential oils (e.g., terpenes) such as from 0% to 80%, usually from 10% to 70% by weight, the essential oils themselves being volatile odoriferous compounds and also serving to dissolve the other components of the perfume.
In the present invention the precise composition of the perfume is of no particular consequence to cleaning performance so long as it meets the criteria of water immiscibility and having a pleasing odor. Naturally, of course, especially for cleaning compositions intended for use in the home, the perfume, as well as all other ingredients, should be cosmetically acceptable, i.e., non-toxic, hypoallergenic, etc. The instant compositions show a marked improvement in ecotoxocity as compared to existing commercial products.
The water soluble nonionic surfactants utilized in this invention are commercially well known and include the primary aliphatic alcohol ethoxylates, secondary aliphatic alcohol ethoxylates, alkylphenol ethoxylates and ethylene-oxide-propylene oxide condensates on primary alkanols, such a Plurafacs (BASF) and condensates of ethylene oxide with sorbitan fatty acid esters such as the Tweens (ICI). The nonionic synthetic organic detergents generally are the condensation products of an organic aliphatic or alkyl aromatic hydrophobic compound and hydrophilic ethylene oxide groups. Practically any hydrophobic compound having a carboxy, hydroxy, amido, or amino group with a free hydrogen attached to the nitrogen can be condensed with ethylene oxide or with the polyhydration product thereof, polyethylene glycol, to form a water-soluble nonionic detergent. Further, the length of the polyethenoxy chain can be adjusted to achieve the desired balance between the hydrophobic and hydrophilic elements.
The nonionic detergent class includes the condensation products of a higher alcohol (e.g., an alkanol containing about 8 to 18 carbon atoms in a straight or branched chain configuration) condensed with about 5 to 30 moles of ethylene oxide, for example, lauryl or myristyl alcohol condensed with about 16 moles of ethylene oxide (EO), tridecanol condensed with about 6 to moles of EO, myristyl alcohol condensed with about 10 moles of EO per mole of myristyl alcohol, the condensation product of EO with a cut of coconut fatty alcohol containing a mixture of fatty alcohols with alkyl chains varying from 10 to about 14 carbon atoms in length and wherein the condensate contains either about 6 moles of EO per mole of total alcohol or about 9 moles of EO per mole of alcohol and tallow alcohol ethoxylates containing 6 EO to 11 EO per mole of alcohol.
A preferred group of the foregoing nonionic surfactants are the Neodol ethoxylates (Shell Co.), which are higher aliphatic, primary alcohol containing about 9-15 carbon atoms, such as C9-C11 alkanol condensed with 2.5 to 10 moles of ethylene oxide (NEODOL 91-2.5 or -5 or -6 or -8), C12-13 alkanol condensed with 6.5 moles ethylene oxide (Neodol 23-6.5), C12-15 alkanol condensed with 12 moles ethylene oxide (Neodol 25-12), C14-15 alkanol condensed with 13 moles ethylene oxide (Neodol 45-13), and the like.
An especially preferred nonionic system comprises the mixture of a nonionic surfactant formed from a C9-C11 alkanol condensed with 2 to 3.5 moles of ethylene oxide (C9-11 alcohol EO 2 to 3.5:1) with a nonionic surfactant formed from a C9-C11 alkanol condensed with 7 to 9 moles of ethylene oxide (C9-C11 alcohol EO 7 to 9:1), wherein the weight ratio of the C9-C11 alcohol EO 7 to 9:1 to the C9-C11 alcohol EO 2 to 3.5:1 is from 8:1 to 1:1 from preferably 6:1 to 3:1.
Additional satisfactory water soluble alcohol ethylene oxide condensates are the condensation products of a secondary aliphatic alcohol containing 8 to 18 carbon atoms in a straight or branched chain configuration condensed with 5 to 30 moles of ethylene oxide. Examples of commercially available nonionic detergents of the foregoing type are C11-C15 secondary alkanol condensed with either 9 EO (Tergitol 15-S-9) or 12 EO (Tergitol 15-S-12) marketed by Union Carbide.
Other suitable nonionic detergents include the polyethylene oxide condensates of one mole of alkyl phenol containing from about 8 to 18 carbon atoms in a straight- or branched chain alkyl group with about 5 to 30 moles of ethylene oxide. Specific examples of alkyl phenol ethoxylates include nonyl phenol condensed with about 9.5 moles of EO per mole of nonyl phenol, dinonyl phenol condensed with about 12 moles of EO per mole of phenol, dinonyl phenol condensed with about 15 moles of EO per mole of phenol and di-isoctylphenol condensed with about 15 moles of EO per mole of phenol. Commercially available nonionic surfactants of this type include Igepal CO-630 (nonyl phenol ethoxylate) marketed by GAF Corporation.
Also among the satisfactory nonionic detergents are the water-soluble condensation products of a C8-C20 alkanol with a heteric mixture of ethylene oxide and propylene oxide wherein the weight ratio of ethylene oxide to propylene oxide is from 2.5:1 to 4:1, preferably 2.8:1 to 3.3:1, with the total of the ethylene oxide and propylene oxide (including the terminal ethanol or propanol group) being from 60-85%, preferably 70-80%, by weight. Such detergents are commercially available from BASF-Wyandotte and a particularly preferred detergent is a C10-C16 alkanol condensate with ethylene oxide and propylene oxide, the weight ratio of ethylene oxide to propylene oxide being 3:1 and the total alkoxy content being about 75% by weight.
Condensates of 2 to 30 moles of ethylene oxide with sorbitan mono- and tri-C10-C20 alkanoic acid esters having a HLB of 8 to 15 also may be employed as the nonionic detergent ingredient in the described composition. These surfactants are well known and are available from Imperial Chemical Industries under the Tween trade name. Suitable surfactants include polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene (20) sorbitan trioleate and polyoxyethylene (20) sorbitan tristearate.
Other suitable water-soluble nonionic detergents are marketed under the trade name xe2x80x9cPluronicsxe2x80x9d. The compounds are formed by condensing ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol. The molecular weight of the hydrophobic portion of the molecule is of the order of 950 to 4000 and preferably 200 to 2,500. The addition of polyoxyethylene radicals to the hydrophobic portion tends to increase the solubility of the molecule as a whole so as to make the surfactant water-soluble. The molecular weight of the block polymers varies from 1,000 to 15,000 and the polyethylene oxide content may comprise 20% to 80% by weight. Preferably, these surfactants will be in liquid form and satisfactory surfactants are available as grades L 62 and L 64.
One of the short chain amphiphile which is used in the instant floor cleaning composition is not a surfactant and is characterized by the formula:
R1O (CH2CH2O)nH
wherein R1 is a straight or branched chain alkyl group having 2 to 6 carbon atoms and n is a number from 2 to 8, more preferably 3 to 6 and the amphiphile has an HLB of about 6 to about 9, preferably about 7 to about 8. Preferred amphiphiles have a C6 alkyl group and 2 to 5 EO such as hexanol 5EO.
Another short chain amphiphile which can be used in the instant floor cleaning composition is not a surfactant and is characterized by the formula:
wherein R1 or R2 are a straight or branched chain alkyl group having 2 to 6 carbon atoms and x or w is a number from 2 to 5, more preferably 2 to 4 and y or z is a number from 1 to 4, more preferably 1 to 3 and the amphiphile has an HLB of about 6 to about 9, preferably about 7 to about 8. Preferred amphiphiles have a C6 alkyl group and 2 to 5 EO such as hexanol 5EO such as Emulan(trademark) HE50).
The final essential ingredient in the instant composition is water. The proportion of water in the compositions generally is in the range of 70 wt. % to 99.0 wt. %.
The floor cleaning composition of this invention may, if desired, also contain other components either to provide additional effect or to make the product more attractive to the consumer. The following are mentioned by way of example: Colors or dyes in amounts up to 0.5% by weight; chelating agents such as ethylene diamine tretraacetic acid, ethylene diamine N,N disuccinic acid, methylglycine N,N diacetic acid, glutamic N,N diacetic acid, phosphonic acid and salt thereof; preservatives, such as formalin, 5-bromo-5-nitro-dioxane, 2-bromo-2-nitropropane-1,3-diol, methylisothiazolone, 5-chloro-2-methyl4-isothaliazolin-3-one, 1,3dimethylol-5,5-dimethylhydantoin, iodopropynyl butylcarbamate and mixture thereof; antioxidizing agent such as 2,6-di-tert.butyl-p-cresol and tetradibutyl pentaerithrityl hydroxyhydrocinnamate; UV-light absorber, etc., in amounts up to 2% by weight; and pH adjusting agents, such as sulfuric acid or sodium hydroxide, as needed.
The cleaning compositions are prepared by simple batch mixing at 25xc2x0 C.-30xc2x0 C. The nonwoven fabric is impregnated with the liquid cleaning composition by means of a positive impregnation process. The liquid is positively fed into the water insoluble substrate through a controlled gear pump and injection bar at a ratio of about 5 grams of liquid cleaning composition to about 1 gram of the nonwoven fabric.
The water insoluble substrate is a nonwoven fabric which is formed from 10 wt. % to 90 wt. % of viscose fibers and 10 wt. % to 90 wt. % of polyester fibers such as Spunlaces made by the Dexter Corporation or Jacob Holm. The nonwoven fabric, due to its weight and composition, has high absorption capacity, and in addition allows smooth release of water to the floor and consequently ensures the highest possible mileage. A preferred substrate is a 100 g/sqm spunlace non woven made by Jacob Holm whose composition is about 65% of viscose fiber and about 35% of polyester fiber.
The following examples illustrate liquid cleaning compositions of the described invention. The exemplified compositions are illustrative only and do not limit the scope of the invention. Unless otherwise specified, the proportions in the examples and elsewhere in the specification are by weight.

Floor cleaning wipe comprising preservative


A cartridge envelope for removably accommodating a disc cartridge includes an envelope structure including top and bottom envelope panels 8 and 9, left and right side walls 10 and 11 and a rear wall 12, all molded together to define a cartridge chamber that opens outwardly in a direction counter to the rear wall through an insertion opening 13. At least one cartridge retaining member 17 including a flexible finger is formed in one of the walls 8 to 12 forming the envelope structure for removably retaining the disc cartridge 1 securely inside the cartridge chamber once the disc cartridge 1 has been inserted thereinto.

1. Field of the Invention
The present invention relates to a cartridge envelope for removably accommodating a disc cartridge.
2. Description of the Prior Art
As is well known to those skilled in the art, some types of optical discs such as, for example, magnetooptical discs are operatively accommodated within a disc cartridge of a generally rectangular flattened configuration. Not only to protect the disc cartridge from dusts, but also to provide the disc cartridge with an aesthetically appealing feature in the market, the disc cartridge containing the respective optical disc is placed on the market in the form as accommodated within a protective or storage envelope. This type of cartridge envelope for a standardized size of the disc cartridge is known from, for example, the Japanese Laid-open Patent Publication No. 10-175691, published Jun. 30, 1998 and assigned to the assignee of the present invention.
According to the above mentioned publication, the cartridge envelope is generally made up of four separate component parts including a generally rectangular flat casing, a pivotally supported panel and a pair of lock elements. The casing includes top and bottom envelope panels each having left and right side walls and a rear wall. While the rear wall of the top envelope panel is segmented into two, the top envelope panel is mounted on the bottom envelope panel for sliding motion in a direction parallel to the bottom envelope panel and conforming to the direction of insertion of the disc cartridge into the cartridge envelope and also for pivotal motion between closed and opened positions relative to the bottom envelope panel. The top envelope panel when in the closed position overlays the bottom envelope panel to define a cartridge chamber therebetween with the side walls of the top envelope panel positioned inwardly of the adjacent side walls of the bottom envelope panel.
A cartridge retaining member, which in the above mentioned publication is termed a xe2x80x9clock bodyxe2x80x9d and which is a member separate from any one of the top and bottom envelope panels, is mounted on each of the segmented rear wall portions in a snap-fitted fashion. The cartridge retaining member includes a base body and an elongated elastic element having its opposite ends integral with the base body, a generally intermediate portion of which extends outwardly from the base body to depict a generally C-shaped configuration to thereby define an elastic protrusion. Within this prior art cartridge envelope, the elastic protrusions of the respective cartridge retaining members on the segmented rear wall portions protrude inwardly relative to each other and into the cartridge chamber so that, as the disc cartridge is inserted into the cartridge chamber, the elastic protrusions can be inwardly deformed in sliding contact with the respective side walls of the disc cartridge and finally snapped into associated positioning recesses in the disc cartridge that are disposed inside the disc player for engagement therewith to retain the disc cartridge in position inside the disc player. With the elastic protrusions engaged in the associated positioning recesses in the disc cartridge, the latter can be securely retained in position inside the cartridge chamber of the cartridge envelope.
In practice, however, the cartridge retaining members disclosed in the above mentioned publication are not only complicated in shape, but time-consuming and expensive to mount the cartridge retaining members on the segmented wall portions of the top envelope panel which are also complicated in shape and structure. Also, manufacture of the prior art cartridge retaining members requires the use of a complicated and expensive mold assembly. Consequently, the prior art cartridge envelope is expensive to manufacture.
The above mentioned publication also discloses, as prior art to the invention thereof, a cartridge envelope generally similar to that described above, except that the top envelope panel is fixed relative to the bottom envelope panel. Specifically, this cartridge envelope comprises top and bottom envelope halves that are joined together to define the cartridge chamber therein. A cartridge retaining member generally similar in shape to that described above is fixedly mounted on each of opposite side walls of the cartridge envelope and functions in a manner similar to that described. Since this cartridge retaining member is a member separate from any of the top and bottom envelope halves, the use of a complicated mold assembly is necessitated and the cartridge retaining member itself is complicated in shape, resulting in increase of the cost of manufacture of the cartridge envelope as a whole.
Accordingly, the present invention has been devised to substantially eliminate the above discussed problems and disadvantages inherent in the prior art cartridge envelope and is intended to provide an improved cartridge envelope having a capability of securely retaining the disc cartridge once it has been inserted into the cartridge envelope, which envelope can be manufactured in the form of a unitary structure to thereby reduce the cost of manufacture thereof.
Another important object of the present invention is to provide an improved cartridge envelope wherein at least one cartridge retaining member is formed integrally with a wall portion of the envelope structure to thereby simplify the structure of the cartridge envelope.
In order to accomplish these and other objects of the present invention, there is provided a cartridge envelope for removably accommodating a disc cartridge, which includes an envelope structure including top and bottom envelope panels, left and right side walls and a rear wall, all molded together to define a cartridge chamber that opens outwardly in a direction counter to the rear wall through an insertion opening. At least one cartridge retaining member formed in one of the walls forming the envelope structure for removably retaining the disc cartridge securely inside the cartridge chamber once the disc cartridge has been inserted thereinto.
Preferably, the cartridge retaining member is of one-piece structure including a flexible finger and a retaining protuberance formed on the flexible finger so as to protrude inwardly of the cartridge chamber. The retaining protuberance is engageable with an outer surface of the disc cartridge, inserted into the cartridge chamber, to retain the disc cartridge securely inside the cartridge chamber.
One of the positioning recesses disposed generally in the disc cartridge for cooperation with corresponding positioning pins disposed inside the disc player to retain the disc cartridge in position inside the disc player relative to an optical read/write head may be utilized for receiving the retaining protuberance to thereby securely retain the disc cartridge inside the cartridge chamber of the cartridge envelope.
In one preferred embodiment of the present invention, the flexible finger may be supported in a cantilever fashion and the retaining protuberance is formed on a free end of the flexible finger.
In another preferred embodiment of the present invention, the opposite side walls of the envelope structure may have a wall thickness greater than that of the top and bottom panels thereof and each of the opposite side walls may have an inner surface formed with a generally U-sectioned trim groove at a position intermediate of the thickness thereof so as to extend lengthwise of the associated side wall from a front end thereof adjacent the insertion opening to a location spaced a distance inwardly from the rear wall.
In any event, at least one of the opposite side walls of the envelope structure preferably has a portion thereof recessed inwardly to provide a thin-walled portion, and the cartridge retaining member is to be formed in that thin-walled portion with the flexible finger displaceable within the recess so formed in the side wall.


A device for delivering a fluid to a patient, including an exit port, a dispenser for causing fluid from a reservoir to flow to the exit port, a local processor programmed to cause a flow of fluid to the exit port based on flow instructions from a separate, remote control device, and a wireless receiver connected to the local processor for receiving the flow instructions. The device also includes a housing free of user input components for providing flow instructions to the local processor, in order to reduce the complexity and costs of the device so that the device lends itself to being disposable in nature. A system and a kit are also described that include the fluid delivery device, a separate, remote control device, and accessories for transcutaneous delivery of fluid medications. Methods of utilizing the fluid delivery device to infuse fluid medications are additionally disclosed.

The present invention relates generally to medical devices, systems and methods, and more particularly to small, low cost, portable infusion devices and methods that are useable to achieve precise, sophisticated, and programmable flow patterns for the delivery of therapeutic liquids to a mammalian patient.
Today, there are numerous diseases and other physical ailments that are treated by various medicines including pharmaceuticals, nutritional formulas, biologically derived or active agents, hormonal and gene based material and other substances in both solid or liquid form. In the delivery of these medicines, it is often desirable to bypass the digestive system of a mammalian patient to avoid degradation of the active ingredients caused by the catalytic enzymes in the digestive tract and liver. Delivery of a medicine other than by way of the intestines is known as parenteral delivery. Parenteral delivery of various drugs in liquid form is often desired to enhance the effect of the substance being delivered, insuring that the unaltered medicine reaches its intended site at a significant concentration. Also, undesired side effects associated with other routes of delivery, such as systemic toxicity, can potentially be avoided.
Often, a medicine may only be available in a liquid form, or the liquid version may have desirable characteristics that cannot be achieved with solid or pill form. Delivery of liquid medicines may best be accomplished by infusing directly into the cardiovascular system via veins or arteries, into the subcutaneous tissue or directly into organs, tumors, cavities, bones or other site specific locations within the body.
Parenteral delivery of liquid medicines into the body is often accomplished by administering bolus injections using a needle and syringe, or continuously by gravity driven dispensers or transdermal patch technologies. Bolus injections often imperfectly match the clinical needs of the patient, and usually require larger individual doses than are desired at the specific time they are given. Continuous delivery of medicine through gravity feed systems compromise the patient""s mobility and lifestyle, and limit the therapy to simplistic flow rates and profiles. Transdermal patches have special requirements of the medicine being delivered, particularly as it relates to the molecular structure, and similar to gravity feed systems, the control of the drug administration is severely limited.
Ambulatory infusion pumps have been developed for delivering liquid medicaments to a patient. These infusion devices have the ability to offer sophisticated fluid delivery profiles accomplishing bolus requirements, continuous infusion and variable flow rate delivery. These infusion capabilities usually result in better efficacy of the drug and therapy and less toxicity to the patient""s system. An example of a use of an ambulatory infusion pump is for the delivery of insulin for the treatment of diabetes mellitus. These pumps can deliver insulin on a continuous basal basis as well as a bolus basis as is disclosed in U.S. Pat. No. 4,498,843 to Schneider et al.
The ambulatory pumps often work with a reservoir to contain the liquid medicine, such as a cartridge or syringe, and use electro-mechanical pumping or metering technology to deliver the medication to the patient via tubing from the infusion device to a needle that is inserted transcutaneously, or through the skin of the patient. The devices allow control and programming via electromechanical buttons or switches located on the housing of the device, and accessed by the patient or clinician. The devices include visual feedback via text or graphic screens, such as liquid crystal displays known as LCD""s, and may include alert or warning lights and audio or vibration signals and alarms. The device can be worn in a harness or pocket or strapped to the body of the patient.
Currently available ambulatory infusion devices are expensive, difficult to program and prepare for infusion, and tend to be bulky, heavy and very fragile. Filling of these devices or their reservoirs can be difficult and require the patient to carry both the intended medication as well as filling accessories when traveling or even just going to work. The accuracy and safety requirements of these devices are extremely important, based both on the medicine being delivered and the condition of the patient. Therefore, the devices require specialized care, maintenance and cleaning to assure proper functionality and safety for their intended long term use. The devices are usually sold for $4,000 to $6,000 requiring maintenance of the device for four or more years to justify the expenditure. Also due to the cost, replacement devices are not easily available or practical. Any damage to the device, such as that caused by it being dropped, result not only in the costs of repair or replacement, but also in a period of discontinued therapy. The high cost of the device is a concern of healthcare providers who approve and prescribe the use of the device, limiting the expansion of the patient populations and therapies for which the devices can be used.
Clearly, therefore, there is a need for a programmable and adjustable infusion system that is precise and reliable and can offer clinicians and patients a small, low cost, light weight, simple to use alternative for parenteral delivery of liquid medicines.
The applicant has determined that a sophisticated ambulatory infusion device that can be programmed to reliably deliver variable flow profiles of liquid medications, yet is small, light weight and low cost, is needed. Smaller and lighter devices are easier to carry and are more comfortable for the patient, even allowing the device to be adhesively attached to the patient""s skin similar to a transdermal patch. An inexpensive device allows greater flexibility in prescribing the device for use by reducing the financial burden on healthcare insurance providers, hospitals and patient care centers, as well as patients themselves. In addition, low cost devices make more practical the maintenance of one or more replacement devices. If the primary device is lost or becomes dysfunctional, availability of the replacement avoids costly expedited repair and down time.
Aspects of the present invention will enable cost reductions significant enough to make the entire device disposable in nature, being replaced as frequently as every two to five days. A disposable device allows the medication to be prefilled by the manufacturer and does not need the routine cleaning and maintenance required by long term devices, greatly simplifying use for the patient. Similar to disposable cameras which have become increasingly popular in recent years, another benefit is that each time a disposable fluid delivery device is purchased, it is the latest or state of the art technology. Long term use devices may be outdated in a year when a new version is available from the manufacturer, just twenty five percent of the life expectancy of the original device.
The present invention, therefore, provides a device for delivering fluid to a patient, including an exit port assembly adapted to connect to a transcutaneous patient access tool, a dispenser for causing fluid from a reservoir to flow to the exit port assembly, a local processor connected to the dispenser and programmed to cause a flow of fluid to the exit port assembly based on flow instructions from a separate, remote control device, and a wireless receiver connected to the local processor for receiving the flow instructions from a separate, remote control device and delivering the flow instructions to the local processor. The device also includes a housing containing the exit port assembly, the dispenser, the local processor, and the wireless receiver. The housing is free of user input components for providing flow instructions to the local processor in order to reduce the size, complexity and costs of the device, such that the device lends itself to being disposable in nature.
According to one aspect of the present invention, the flow instructions cause a predetermined rate of fluid flow for a predetermined period. According to another aspect, the predetermined rate of fluid flow comprises a basal rate.
According to another aspect of the present invention, the flow instructions cause a predetermined volume of fluid to flow for a predetermined period. According to an additional aspect, the predetermined volume comprises a bolus volume.
According to an additional aspect, the device includes a least one user interface component accessible from an exterior of the housing for causing a predetermined volume of fluid to flow for a predetermined period, independently of the local processor. According to a further aspect, the device includes a least one user interface component accessible from an exterior of the housing for occluding flow to the exit port assembly.
According to another aspect of the present invention, the device includes a power supply connected to the local processor. According to an additional aspect, the device includes a transmitter connected to the local processor for transmitting information from the local controller to a separate, remote control device. According to still a further aspect, the housing is free of user output components for providing information from the local processor. According to a further aspect, the exit port assembly includes a tubular member for transcutaneously entering a patient. According to still a further aspect, the device includes a reservoir.
The present invention also provides a system including a fluid delivery device as described above, and further including a separate, remote control device including a remote processor, user input components connected to the remote processor for allowing a user to provide instructions to the remote controller, and a transmitter connected to the remote controller for transmitting the instructions to the receiver of the fluid delivery device. Thus, the remote controller allows a user, such as a patient, nurse or doctor, to remotely program the fluid delivery device to provide a desired infusion of fluid into the patient.
The present invention further provides another device for delivering fluid to a patient, including an exit port assembly adapted to connect to a transcutaneous patient access tool, a dispenser for causing fluid from a reservoir to flow to the exit port assembly, a local processor connected to the dispenser and programmed to cause fluid flow to the exit port assembly based upon flow instructions. The local processor is also programmed to provide flow information, and a wireless transmitter is connected to the local processor for transmitting the flow information to a separate, remote control device. A housing contains the exit port assembly, the dispenser, the local processor, and the wireless transmitter, and is free of user output components for providing the flow information from the local processor to a user.
These aspects of the invention together with additional features and advantages thereof may best be understood by reference to the following detailed descriptions and examples taken in connection with the accompanying illustrated drawings.

Devices, systems and methods for patient infusion


Improved switching techniques for controlling three-level current steering DAC cells are disclosed. The techniques include decoupling two current sources, implemented as field-effect transistors (FETs), of a DAC cell both from their respective bias sources and from a load for converting a zero digital input, where the decoupling is performed in a certain order. The techniques also include coupling the current sources to their respective bias sources and to the load for converting a non-zero digital input, where the coupling is also performed in a certain order. The certain order of decoupling and coupling the bias sources and the load to the current sources of a DAC cell are based on the phenomenon of current memory in FETs. Utilizing current memory when operating a DAC cell may allow reducing power consumption while preserving the high performance properties of a three-level current steering DAC.

Real-world analog signals such as temperature, pressure, sound, or images are routinely converted to a digital representation that can be easily processed in modern digital systems. In many systems, this digital information must be converted back to an analog form to perform some real-world function. The circuits that perform this step are digital-to-analog converters (DACs), and their outputs may be used to drive a variety of devices. Loudspeakers, video displays, motors, mechanical servos, radio frequency (RF) transmitters, and temperature controls are just a few diverse examples. DACs are often incorporated into digital systems in which real-world signals are digitized by analog-to-digital converters (ADCs), processed, and then converted back to analog form by DACs. In these systems, the performance required of the DACs will be influenced by the capabilities and requirements of the other components in the system.
Power consumption is an issue that engineers continuously try to improve on. Improvements could be made with respect to reducing power consumption of DACs.

Utilizing current memory property in current steering digital-to-analog converters


A bookbinding system includes an image forming apparatus and a bookbinding apparatus connected to the image forming apparatus. The bookbinding system includes an image forming unit to form an image on a recording sheet; a loading unit to load, as a bookblock stack, plural recording sheets on which images are formed; a bonding unit to form a booklet by bonding a cover with the bookblock stack; a setting unit to set a bookblock size, a cover size, and a finishing size; a cutting unit to cut the booklet bonded together with the cover into the finishing size; a stack thickness detection unit to detect a thickness of the bookblock stack; and a bookbinding permission/inhibition determination unit to determine permission/inhibition of a bookbinding operation based on a stack thickness detection result as well as the bookblock size, the cover size, and the finishing size set by the setting unit.

1. Field of the Invention
The present invention relates to a bookbinding system and a bookbinding apparatus that loads, as bookblock stack (i.e., an inner book part), a plurality of recording sheets discharged from an image forming apparatus, bonds a cover with the bookblock stack, and cuts the bookblock stack bonded together with the cover into a designated size.
2. Description of the Related Art
A conventional bookbinding apparatus performs gluing processing for applying glue to a stack of recording sheets (hereinafter, referred to as "bookblock stack") discharged from an image forming apparatus, bonding processing for bonding a cover with the bookblock stack, and cutting processing for cutting the bookblock stack together with the bonded cover.
As discussed in Japanese Patent Application Laid-Open No. 2005-104063 and Japanese Patent Application Laid-Open No. 2004-209870, a bookbinding system includes an image forming apparatus connected to the bookbinding apparatus.
However, as illustrated in FIG. 48, in a state where a cover is bonded around a bookblock stack, the cover length in a front edge direction varies according to a stack thickness of the bookblock stack. The above-described conventional bookbinding system does not take this variation into consideration.
For example, if a bookblock has a small stack thickness (e.g., if the number of sheets is small), a cutting amount of a cover is large. As illustrated in FIG. 49, if a cut waste 1000 is excessively long, the cut waste 1000 interferes with a waste receiver unit 533. Thus, the waste processing is infeasible.
Furthermore, if the cover length in the front edge direction is long, a bookbinding product (which is not subjected to cutting processing) interferes with a ceiling member 1001 and cannot be discharged as illustrated in FIG. 50.

Bookbinding system and bookbinding apparatus


Compositions and methods for providing a person with an exogenous and therapeutically effective supply of ketones are disclosed. The compositions may consist essentially of (a) purified butyrate (or esters or propionate salts thereof) and (b) purified beta-hydroxybutyrate (or esters or propionate salts thereof). The compositions may further include other pharmacologically active agents, such as acetyl-L carnitine, R-alpha lipoic acid, green tea extract, vitamins, and various combinations of such agents. The methods include providing a person with an exogenous supply of ketones, by orally administering a pharmacologic composition, which is effective to deliver 2000-5000 mg of a short chain fatty acid (e.g., butyrate) and 5000-10,000 mg of ketone (e.g., beta-hydroxybutyrate) on a daily basis.

Ketones (Background)
It is well understood that dietary restriction in the form of calorie deprivation and/or a low carbohydrate/high fat diet (LCHFD) is conducive to ketogenesis. Although hyperketonemia (>0.5 mmol/L of serum ketones), when induced by such dietary programs, has been shown to produce positive effects on biological markers of insulin resistance, serum glucose stabilization, diabetes, obesity, epilepsy, cognitive deficits, inflammation and even cancer, achievement and sustenance of functional serum ketone levels is a very difficult task. Achieving a state of ketosis requires dedication and sacrifice, while enduring states of malaise during energy substrate transition. For some, the achievement of ketosis is more difficult than for others based on metabolic, genetic, environmental, and lifestyle factors combined.
Sustained ketosis is also a state desired by athletes in pursuit of improved performance, as a function of ketones serving as substrates for mitochondrial ATP generation. Research shows that ketones produce as much as 38% more ATP per unit carbon than glucose as substrates of the TCA cycle. In addition, research shows ATP generation from ketones as substrates in the mitochondria instead of glucose results in fewer free radical by-products. Furthermore, ketones are shown to induce transcription and subsequent synthesis of endogenous antioxidants, thereby priming the generation of intracellular glutathione and other endogenous antioxidants to produce a proactive protection against oxidative stress.
Athletes in ketosis and under physical load are shown to operate at full power output with a lower VO2 max than those utilizing glucose (carbohydrate) as a primary source of ATP. When at elevated serum levels indicative of ketosis, ketones are also known to spare muscle (anticatabolic) when under stress, including stress caused by nutrient deprivation. Although ketosis is a metabolic state that does not fit optimally for everyone who attempts to achieve it, there are pharmacological benefits of ketones, such as beta-hydroxyl-butyrate/beta-hydroxybutyrate (BHB) and acetoacetate when they exist in hyperketonemic states. Healthy ketosis is represented by a state where ketones measure in the range 0.4-5.0 mmol/L, while blood sugar remains stable and at around baseline of 4.2-5.0 mmol/L.
Although it is known that ketones serve as substrates for efficient ATP generation, the means by which such ketones also serve as ligands for various receptors, such as hydroxyl carboxylic acid receptors (HCA), are not well understood. BHB is a known HCA2 receptor agonist and, therefore, it is expected to have some neuroprotective activity, vis-à-vis its activity on monocytes and macrophages.
During carbohydrate deprivation, serum glucose declines and the metabolism can shift to fatty acid beta-oxidation and the production of ketones. This is the essence of endogenous ketone induction. Although fatty acids cannot readily cross the blood brain barrier to serve neurons as an energy substrate amid carbohydrate deprivation, ketones are hydrophilic and can cross to serve efficiently as substrates for neuron ATP generation. Ketones can supply in excess of 50% of the brain's energy requirements during periods of glucose scarcity. The scarcity of glucose amid the abundantly available ketone causes cells to increase mitochondrial numbers, induce endogenous antioxidant generation, and activate various other protective mechanisms.
It has further been established that many neurological disorders are associated with impaired mitochondrial activity, compromised mitochondrial numbers, limited endogenous antioxidant status, elevated free radical generation, and oxidation amongst other pathological features and hallmarks. Ketosis has been shown to improve many of these pathological features.
In view of the foregoing, the exogenous supply of ketones may offer a number of pharmacological benefits, including both mental and physical benefits. A daily supply of exogenous ketones would alleviate the stress associated with diet adherence, and would allow for the pharmacological benefits of ketones to continue due to the maintenance of elevated serum ketone levels (despite the temporary or prolonged increment of serum glucose and stored glycogen that may ensue as a function of a meal or few days off a ketogenic cycle). An exogenous supplement of ketones would also provide an immediate and efficient transition back to a ketogenic lifestyle, without the associated energy deficit that is typically associated with the cell-switch-back to serum ketones and fat as an energy (ATP) substrate. Metabolic support during energy substrate scarcity would be another substantial benefit of an exogenous ketone supply, particularly in the context of calorie or carbohydrate deprivation for weight management or therapy of other types. An exogenously supply of ketones would further serve as a bridging energy source during a low-carbohydrate diet and fluctuations in dietary habits, whether those shifts are long-term initiatives or short-term breaks. An exogenous supply of ketones would serve to avert the state of malaise that is often attendant to a calorie/carbohydrate deprived state, and would improve appetite control and support cognitive alertness.
Butyrate (Background)
Short chain fatty acids, also known as volatile fatty acids, are those typically produced by the microbial community of the intestine. These microbes are often referred to as probiotics or microbiota. Such microbes comprise a significant component of the immune system. These symbiotic microbes produce short chain fatty acids from dietary fiber, i.e., fatty acids that serve as signaling ligands for various receptors involved in inflammatory control, including the HCA2 receptor (the above described beta-hydroxybutyrate (ketone) serves as an agonist for such receptor as well).
The short chain fatty acids of the intestinal lumen include most abundantly, butyrate, propionate, and acetate. Research shows that butyrate fed mice remain lean (despite dietary calorie load); avoid metabolic problems; have increased energy expenditure in the form of body heat generation; and tend to have higher physical activity. Butyrate has been shown to lower serum cholesterol in various studies and by as much as 25% in some studies, and reduce serum triglycerides by as much as 50% compared to controls. Butyrate has further been shown to lower fasting insulin by nearly 50%, and increase insulin sensitivity by as much as 300%. Still further, butyrate administration has been shown to improve appetite and food portion control.
Research has further shown that butyrate is a key fuel for epithelial cells of the intestinal tract and that it may improve gut lining integrity. Similar to BHB, butyrate is an inhibitor of HDAC to induce global changes in genetic transcription of genes encoding oxidative stress resistance. This down regulation of gene transcription results in improved protection from free radical damage associated with strained or extreme metabolic conditions (and environmental toxins). This genetic optimization provided by butyrate also includes neuroprotection, similar to that exhibited by BHB.
Still further, lumen butyrate has been shown to directly preserve gut friendly bacteria in the microbiota, while adversely affecting pathogenic bacteria like Escherichia coli, Salmonella spp. and Campylobacter spp. Passive absorption of water in the colon depends on short chain fatty acid availability. Butyrate has been shown to play a role in healthy peristalsis to help normalize movement in cases of constipation or diarrhea. Butyrate serves to support optimal hydration and optimal bowel elimination function. Butyrate has also been shown to exhibit trophic effects on intestinal cell proliferation, improving villi, and general lining health. In addition, butyrate has been shown to be a potent promoter of intestinal regulatory T cells establishing yet another immune regulating mechanism that promotes better inflammatory control at the mucosal lining. Promotion of gastrointestinal health provides a formidable platform for improved general and systemic health.
To compound the benefits offered by ketosis (as described above), it is known from the literature that butyrate induces FGF21 in serum, liver and adipocytes, which in turn stimulates fatty acid oxidation and hepatic ketone production. This serves as an inducing signal for ketosis, along with butyrate itself, thereby serving as a direct substrate for ketone production and energy generation. In short, butyrate serves as a significant synergistic force for ketosis induction; BHB ligand interactions and pharmacology; and general health, fitness and performance support.
As discussed above, an exogenous supply of ketones, such as BHB, will provide an immediate alternative energy (ATP) source during periods of calorie or carbohydrate deprivation. However, concurrent butyrate supplementation in the form of sodium, calcium or potassium butyrate (or its esters) will prompt the body to induce endogenous ketone synthesis; will serve as a ligand to stimulate receptors that the ketone will act on; will contribute to the improvement of insulin and general metabolic health; will support inflammatory and general immune system health; will improve gastrointestinal health and integrity—all in parallel with the benefits that concurrent supplementation of the sister ketone molecule will provide.
As the following will demonstrate, the compositions and methods of the present invention will be very useful for providing an exogenous supply of ketones, to provide a person with the numerous pharmacologic benefits described herein.

Butyrate and beta-hydroxybutyrate compositions