Zeolite based material and a method for making the zeolite, comprising a zeolite having a silica/alumina ratio of at least 300 and a surface area of 250 m2/g and no greater than about 20 parts, by weight, of a silica binder. The combination of properties this zeolite based material exhibits includes the following: (1) a modulus of rupture of at least 1500 psi; (2) a surface area of at least 100 m2/g; (3) a coefficient of thermal expansion of less than about +/xe2x88x9210 ppm/xc2x0 C.; and, (4) a thermal shock resistance of at least 850xc2x0 C. The zeolite-based material can include a third component, specifically a gamma alumina having a specific surface area of greater than 100 m2/g.

1. Field of the Invention
The present invention relates to a improved zeolite/silica/alumina material and a method for making such material. In particular it relates to a zeolite/silica/alumina composite material exhibiting a high strength and a high surface area.
2. Background and Discussion of the Related Art
The Clean Air Act of 1970 requires that a catalytic converter be installed on an automobile to purify the exhaust gas stream. The catalytic converter removes unburned gasoline, carbon monoxide and nitrogen oxides simultaneously in the exhaust stream. A conventional catalytic converter consists of a multi-channel ceramic honeycomb and includes a high surface area material that is, along with the actual catalytic material (e.g., three-way catalyst (TWC)), washcoated onto the ceramic material. The monolithic ceramic honeycomb provides a strong substrate for the catalyst, in addition to meeting mechanical and thermal requirements. However, acting as an inert structure, the catalyst substrate does not participate in the chemical reactions for removal of unburned hydrocarbons, carbon monoxide and nitrogen oxides.
U.S. Pat. No. Re. 34,804 discloses the formation of extruded zeolite honeycomb bodies that include a permanent binder silicone resin component. An improved method for making the zeolite body is disclosed in U.S. Pat. No 5,492,883 (Wu) wherein the zeolite material is mixed with an aqueous silicone resin emulsion and, a temporary binder, such as methylcellulose, and the mixture is extruded to form a green honeycomb body, which is thereafter dried and sintered. Another improved method for making a zeolite body is disclosed in U.S. Pat. No. 5,633,217 (Lynn), wherein it is discloses the use of a dibasic ester as the solvent for the silicone resin and the use of a methylcellulose temporary binder. Finally, U.S. Pat. No. 5,565,394 (Lachman et al.) discloses improved zeolite bodies that include a thermal expansion control component such as calcium silicate, permanent binder such as silica or alumina and a temporary binder such as methylcellulose. Although the zeolites disclosed in the Wu, Lynn and Lachman references are not inert and are capable of use as a catalyst material, they each require the application of a precious metal washcoat in order to function as a three-way catalyst capable of the conversion of hydrocarbons, nitrogen oxides and carbon monoxide into their nontoxic gaseous counterparts.
For zeolite based materials to be used as monolithic honeycombs at increased temperatures ( greater than 300xc2x0 C.) the zeolite material should exhibit the following combination of properties, not currently possessed by conventional zeolite bodies: high strength, high surface area, high thermal stability (i.e. high thermal shock resistance) and a low coefficient of thermal expansion. There is, accordingly, a clear need for, and thus an object of the present invention is to provide, a zeolite material exhibiting the aforementioned requisite properties.
The object of the present invention is to solve the above problems of the prior art and to provide high strength, high surface area zeolite material exhibiting a high thermal stability and low thermal expansion.
Specifically, the invention is directed at a zeolite based material for use as a catalyst substrate, adsorber or catalyst carrier comprising a zeolite having a silica/alumina ratio of greater at least 300 and a surface area of 250 m2/g and no greater than about 20 parts, by weight, of a silica binder. The properties this zeolite based material exhibits includes the following: (1) a modulus of rupture of at least 1500 psi; (2) a surface area of at least 100 m2/g; (3) a coefficient of thermal expansion of less than about +/xe2x88x9210 ppm/xc2x0 C.; and, (4) a thermal shock resistance of at least 850xc2x0 C.
In a separate embodiment the zeolite-based material includes a third component, specifically gamma alumina having a specific surface area of greater than 100 m2/g.
This invention also relates to a method for producing an extruded honeycomb monolith having the aforementioned high strength and surface area properties, comprising mixing into a substantially homogeneous body the following components: (1) a zeolite having a silica/alumina ratio of at least 300 to 1 and a surface area of at least 250 m2/g; (2) no greater than 20 parts, by weight, of a silica binder derived from using a resin/solvent mixture having a ratio ranging between from 2/1 to 4/1; (3) a temporary binder; and, (4) water. Following mixing of the raw materials, the method involves extruding the mixture to form a green honeycomb structure, and then drying the structure for a time sufficient to form a crack-free dry structure. Once the extruded body is dried, the method next involves heating the dried honeycomb structure in a nitrogen atmosphere, to a first temperature of at least 500xc2x0 C., cooling to ambient, and thereafter, heating, in air, to a second temperature of at least 850xc2x0 C. to form a sintered structure.
xe2x80x9cThe product of the present invention is a zeolite body for use as an adsorber or catalyst carrier, specifically a zeolite-based material wherein the zeolite exhibits a silica/alumina ratio of at least more than 300 and a surface area of at least 250 m2/g. Expressed in parts by weight, the zeolite based bodies, according to the invention, characteristically contain between about 30 to 90 parts, by weight, zeolite and not more than 20 parts, by weight, silica binder.xe2x80x9d
Typically, zeolites comprise large particles on the order of several microns and exhibit a regular array of accessible micropores, a combination that provides the high surface attribute of zeolites; a feature that is retained by zeolites after sintering. Generally, such catalyst support and adsorber applications require substantial overall surface areas of at least 20 m2/g, preferably greater than 100 m2/g, and most preferably greater than 150-200 m2/g. The inventive zeolite based body is capable of being extruded into a high cell density, thin walled monolithic body, e.g., a honeycomb structure exhibiting at least 400 cells/in2, exhibiting surface areas of at least 200 m2/g, with surface areas in excess of 250 m2/g being readily attainable.
As detailed above, the zeolite component is desirably a high silica-containing zeolite exhibiting a SiO2/Al2O3 molar ratio of at least 300. The presence of a zeolite having the requisite high silica/alumina ratio provides for a zeolite-based material having both a thermal stability at those high temperatures typically experienced in the exhaust environment, and the expected ability to adsorb and desorb hydrocarbons. In other words, the high silica content of the zeolite provides the composite with the ability to maintain its structure at high temperatures. On the other hand, the presence of a low alumina content in the zeolite ensures that the zeolite will not experience the type of moisture problems typically associated with zeolites having high alumina content; high alumina zeolites typically de-aluminate in the presence of moisture at high temperatures. Furthermore, the zeolites crystalline silica phase is maintained at high temperatures and is responsible for the negative CTE characteristic that compensates to reduce the overall thermal expansion of the composite body. In sum, the inventive material provides for a zeolite adsorber material that allows the automotive exhaust system designer a certain degree of flexibility in exhaust system design; adsorber material having increased thermal stability.
Suitable zeolites include any silica-based zeolite having the requisite very high silica/alumina ratio. Useful high silica/alumina ratio-containing zeolites for the practice of the invention can be found among the zeolites selected from the following: mordenite, ultrastabilized Y (USY), ZSM-5, ZSM-8, ZSM-11, ZSM-12, Hyper Y, beta-zeolites, H-ferrierite, H-offretite, faujasite, X zeolite, type L zeolite, mazzite, EMC-2, and combinations of these, preferably silicalite, and any of the natural zeolites including erionite, clinoptilolite, chanazite and phillipsite. One commercially available zeolite having the requisite high silica property is CBV 3002 available from the PQ Corporation.
In addition to a high surface area, other features of this zeolite body that make it suitable for use as an adsorber material include its relatively low thermal expansion and high thermal stability; less than 10 ppm/xc2x0 C., preferably 5 ppm/xc2x0 C., and thermal stability up to at least 1000xc2x0 C., respectively. Furthermore, catalyst support applications and filter/adsorber applications preferably require a flexural strength in excess of 1500 psi. The zeolite body of the instant invention exhibits flexural and crushing strengths that exceed this value and are on the order of greater than about 1500 psi, with MOR""s in excess of 3500 psi being attainable.
A second embodiment of the inventive zeolite body comprises the inclusion of a third component, a gamma alumina having a surface area of greater than 100 m2/g. The gamma alumina component having the high surface area also contributes to result in an overall zeolite-based body that is well within the surface area requirements of many catalyst support applications. Expressed in parts by weight, the zeolite/silica/alumina bodies, according to the invention, characteristically contain between about 85 to 90 parts, by weight, zeolite and 10-15 parts, by weight, silica binder, and up to 50, parts, by weight, alumina.
Although the presence of silica prevents the incorporation of PGM catalysts into the extruded zeolite substrate, due to silica""s known PGM incompatibility, the presence of alumina in this embodiment provides the zeolite-based composite structure the support material function for non-PGM catalysts. Specifically the gamma alumina provides the necessary sites to enable binding of transition metal oxide catalyst to the structure, such that the composite will have enhanced catalytic activity and lifetimes over zeolite-only structures, when used in the certain harsh environments typically associated with high temperature, such as seen in chemical processing applications. Additionally, the alumina, whereby the transition metal oxides are typically sited is porous enough and exhibits a high enough surface area porous structure so as to inhibit sintering of the metal oxides present and to provide for the accessibility of the transition metal oxides to the reactant stream.
Gamma alumina suitable for use in the formation of this composite include those aluminas that after calcining provide the requisite gamma alumina phase and exhibit a sufficiently high surface area suitable for functioning as the catalytic support material. A suitable commercially available gamma alumina having the requisite high surface area characteristic is GL-25 supplied by LaRoche Industries.
In another embodiment, the zeolite body should include a stabilized high surface area alumina. The stabilized alumina should include an amount of stabilizing agent selected from the group consisting of lanthanum oxide (La2O3) or it equivalents, including barium oxide, strontium oxide and yttrium oxide. These stabilizing agents are known for stabilizing the specific surface area of the alumina, which in its pure form is typically unstable at high temperatures. Specifically, the stabilizing agents inhibit the phase transformation of alumina at high temperatures, thereby increasing the high temperature stability of the alumina. The stabilizing agents are typically included in the alumina as a pre-dopant prior to the batching of the composite, and more preferably they are added to the composite after firing via an impregnation process.
A preferred stabilizing agent for the alumina is lanthanum oxide (La2O3), which is included by impregnation into the gamma alumina component of the composite. Lanthanum impregnation is such that the composite includes lanthanum oxide in the weight range of 0.5-20, parts, by weight, with respect to the alumina component amount. If lanthanum is added in an amount less than such range, then the beneficial effect of increase in activity due to the lanthanum addition is not observed.
For catalyst applications, porosity, as measured by total porosity, of the zeolite/alumina composite should be sufficient to permit access to the transition metal oxide catalyst through the walls. For adsorber applications, porosity, as measured by average pore size, should be sufficient to allow the support to function effectively as an adsorber. The range of choice, for total porosity and average pore size, may be varied to accommodate the proposed catalyst or adsorber applications. Porosity is dependent upon the raw materials and the firing temperature, the higher the temperature the more dense the resulting structure. For catalyst and/or catalyst support applications, the inventive zeolite structures may exhibit a total porosity of about at least about 30%, along with sub micron average pore sizes.
In addition to its use as a simple adsorber structure, as detailed above, the inventive high silica/alumina zeolite material can be used as a catalyst substrate, specifically, as a replacement for cordierite. Alternatively, the inventive zeolite can be used as a catalyst substrate in those applications where it performs the additional function of adsorbing hydrocarbon during the cold-start stage (e.g., Bag I and II emissions).
In the first catalyst substrate embodiment, the zeolite honeycomb substrate is washcoated with a conventional three-way catalyst, and catalyst system performs in the same manner as a regular cordierite supported three-way catalyst system. Suitable catalytic materials for supporting on the high silica/alumina zeolite substrate include platinum, palladium, rhodium and iridium. The zeolite substrate is comprised of a zeolite material that exhibits high thermal stability under automotive exhaust conditions. Suitable zeolites include those selected from the following materials: mordenite, ultrastabilized Y (USY), ZSM-5, ZSM-8, ZSM-11, ZSM-12, all exhibiting a silica/alumina ratio of 300 and above.
In the second embodiment, the zeolite substrate is washcoated with an oxidation catalyst; suitable oxidation catalysts including platinum, palladium rhodium or iridium. The washcoated zeolite catalyst functions as a hydrocarbon trap for reducing hydrocarbon emissions during the cold-start stage. Zeolite material choices for the substrate include the following: beta-zeolite, USY and ZSM-5 and mordenite, all exhibiting the requisite high silica/alumina ratio of 300 or above. These large pore zeolites exhibit a large capacity for the adsorption of hydrocarbon, while at the same time exhibiting requisite thermal stability to survive the harsh environment in an automotive exhaust stream. Once the washcoated oxidation catalytic material reaches a sufficient material it functions to destroy harmful hydrocarbon molecules by oxidizing these molecules, with oxygen present in automotive exhaust stream, to environmentally benign molecules such as water and carbon dioxide.
The general method of producing porous sintered substrates, as one skilled in the art can appreciate, is by mixing batch materials, blending the mixture, forming a green body, and subsequently sintering the green body to a hard porous structure. In the manner of making the body various lubricants, such as zinc stearate and sodium stearate, and organic binders are added to the batch during the mixing step to provide viscosity control and strength prior to firing and porosity to the after fired structure.
A particularly preferred method for producing the composite of the invention described herein, an extruded honeycomb monolith having a high surface area, comprises mixing into a substantially homogeneous body certain raw materials capable of forming the aforementioned composite. Specifically, the raw materials that will form a composite include a zeolite raw material that exhibits a silica/alumina ratio of at least 300 to 1 and a surface area of at least 250 m2/g, a silica binder exhibiting a resin/solvent ratio of between 2/1 to 4/1 and, optionally, a gamma alumina component exhibits a specific surface area of greater than 100 m2/g. As is standard in the formation of ceramic structures, the batch mixture should include a temporary organic binder and water. The preferred method of forming the body includes extruding the body to form a green honeycomb structure. Once formed into a honeycomb body the extruded green body is then dried by heating the structure for a time period sufficient to form a crack-free dry structure.
The drying step is accomplished in a number of different ways. One embodiment involves placing the structure in an oven at a temperature in the range of 50 to 100xc2x0 C., preferably, at a temperature in the range of 90 to 100xc2x0 C. for periods of up to 4 days. In another, slightly modified, embodiment the drying step is accomplished by placing the green structure in a relative humidity controlled oven (e.g., 90% relative humidity) for similar time periods and temperatures as for the aforementioned standard oven-drying embodiment. In a third embodiment, the drying step is accomplished by placing the green structure in a dielectric oven for a period of time sufficient to form a crack-free, self-supporting structure, preferably, a period of no greater than 60 minutes, more preferably for a period of 5 to 30 minutes.
Sintering of the dried honeycomb structure involves heating or sintering the honeycomb for a time period sufficient to form a sintered structure having a high surface area. Specifically the sintering comprises heating the honeycomb in a nitrogen atmosphere, at a rate 10-25xc2x0 C./hr, to a first temperature of at least 500xc2x0 C., preferably this temperature is then maintained for period of up to 10 hours, more preferably 4 hours. Following this nitrogen pretreatment firing, the honeycomb is cooled to ambient temperature. Once ambient temperature is attained, the honeycomb is heated, in air, to a second temperature of at least 850xc2x0 C., preferably 1100xc2x0 C. This second air-heating step, to at least 850xc2x0 C., may involve two distinct heating steps: (1) a first heating step, at a rate of between 10-25xc2x0 C./hr to 500xc2x0 C., whereupon the temperature is held for period of time; and, (2) and a second heating step from 500xc2x0 C. to at least 850xc2x0 C., at a rate of about 50xc2x0 C./hr, whereupon the temperature is again held for a period of time. For both air-heating steps, the temperature-holds are preferably maintained for period of up to 10 hours, and more preferably 4 hours.
The pre-treatment nitrogen heating step is thought to result in sintered structures exhibiting an increased MOR over those bodies not subject to this pre-treatment step. While not intending to be limited by theory it is thought that the nitrogen pre-treatment produces a gradual slow burnout of the organic binder that does not disrupt the microstructure of the zeolite bodies, thus allowing for easier densification of the zeolite body at the later achieved higher firing temperatures.
The purpose of the organic binder is to provide plasticity during forming, and some green strength after drying. Organic binder according to the present invention refers to cellulose ether type binders and/or their derivatives, some of which are thermally gellable. Some typical organic binders according to the present invention are methylcellulose, hydroxybutylcellulose, hydrobutyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, sodium carboxy methylcellulose, and mixtures thereof. Methylcellulose and/or methylcellulose derivatives are typically used in the practice of the present invention. Methylcellulose, hydroxypropyl methylcellulose, and combinations thereof are especially preferred. Preferred sources of cellulose ethers and/or derivatives thereof, are Methocel A4M, F4M, and F240M from Dow Chemical Co. Methocel A4M is a methylcellulose binder having a gel temperature of 50-55xc2x0 C. and gel strength of 5000 g/cm2 (based on 2% solution at 65xc2x0 C.). Methocel F4M and F240M are hydroxypropyl methylcellulose.

High strength and high surface area catalyst, catalyst support or adsorber compositions


The invention disclosed is a direct driven, smart material actuated servovalve providing very high actuation control bandwidth for moderate to large flow systems. The servovalve is comprised of a valve body and a valve spool, a smart material element such as a piezoelectric, electrostrictive or magnetostrictive material, and a mechanical lever. The lever is mounted to a pivot support in the valve body and is positioned relative to the smart material element and valve spool such that expansion/contraction motion induced into the smart material element enforces motion on the first end of the mechanical lever. This motion is amplified by the lever at the second end of the lever and drives the end of the valve spool. The resulting amplified motion causes the valve spool to shift along its longitudinal axis of sufficient distance to afford high bandwidth valve spool positioning on large flow valves. Localized spool position sensing and control electronics are further added to provide a self-contained, high bandwidth servovalve.

The present invention relates to servohydraulic actuators. More particularly, the present invention pertains to a piezoelectric direct driven servovalve capable of very high bandwidth operation.
For many high load systems hydraulic actuators have remained a necessary and desirable means of device actuation. The control of these actuators is commonly effected through the application of various types of servovalves. In most servovalves a mechanical or electrical signal is utilized to direct the position of a valve spool within a valve housing. The position of the valve spool within the housing determines the flow path(s) between valve ports to direct flow to the ports of a hydraulic actuator thus determining the direction of force application and motion of the actuator.
The need for higher frequency, more precise control of structures and devices has led to ever improving servovalves and systems. Servovalves have evolved from relatively slow acting two stage devices where the first stage is comprised of a pilot valve. The pilot valve is controlled by some low power means such as human force input or a low power electrical signal and shuttles a pressurized fluid or gas supply in a pilot system which thereby displaces a valve spool in a larger flow, power control valve. The power control valve in turn determines the flow direction to a high force, large displacement actuator. The compliance and inertia in the hardware used for pilot valve operation and the compliance and fluid inertia in the pilot fluid system combine to significantly reduce the frequency response of the power control valve to the original system command input.
The need for faster acting systems has led to the development of various single-stage control valves where a single, directly controlled system or device develops the force necessary to shuttle the valve spool in the flow control valve governing the high force actuator.
Substantial increases in control speed and available system bandwidth have been gained through the application of electromagnetic motors. With electrical amplification of the command signal, an electronic amplifier and electromagnetic motor or actuator directly control the position of the servovalve spool. The force available from the electromagnetic device is utilized to directly drive and position the spool, thus supplanting the pilot valve and pilot pressure system formerly used for power valve actuation.
An example of such a system is disclosed in U.S. Pat. No. 5,040,568. In that patent the rotary motion of an electromagnetic motor is applied directly to the spool of a power valve to effect valve control in a directly driven, single-stage manner. The size of the power valve and the magnitude of the power system pressure being controlled determine the amount of valve spool force necessary for valve control, which thereby determines the size of the electromagnetic motor necessary for spool positioning. A significant disadvantage of the use of electromagnetic motors for servovalve actuation is the relatively weak force and energy density of these drives which limits the size and bandwidth of the servovalve. As the electromagnetic motor size increases, performance frequency drops and system control bandwidth becomes limited by the inherent characteristics and performance capabilities of the motor.
In an alternative approach for gaining system control bandwidth, smart materials, such as piezoelectric, electrostrictive, and magnetostrictive materials, have been employed in valve control systems. With smart materials large forces can be generated for very small distances and controlled at very high frequencies.
In U.S. Pat. No. 5,148,735 a piezoelectric or magnetostrictive element operates as the actuation means to valves controlling the fluid in a pilot fluid system. In this approach the smart material elements in combination with the pilot fluid controlling valves act as a pilot valve to a pilot system so to directly control the fluid pressure applied to the ends of the power valve spool. The approach maintains the compliance and inertia of the pilot system, however, which reduces the bandwidth capability inherent to the smart material element.
The use of a piezoelectric element to directly control the position and movement of a valve spool is disclosed in U.S. Pat. No. 6,170,526 B1. In that patent a piezoelectric actuator controls the position of a poppet valve within its valve body. In that patent the poppet valve change in position is equal or comparable to the change in length of the piezoelectric element, which being very small causes the available valve motion to be very small. The small amount of valve movement afforded severely limits the size of the valve and the flow which can be regulated.
There is a need for a high bandwidth servovalve with frequency response substantially beyond that available from electromagnetic actuated valves which is also suitable for substantially larger flow capability than that afforded by the present smart material actuated valves. The invention described herein provides for such a servovalve.
The invention disclosed is a direct driven, smart material actuated servovalve having substantially increased actuation control bandwidth relative to comparably sized flow valves available in the prior art and thereby is suitable for use in moderate to large flow systems as a single-stage servovalve.
The invention incorporates smart materials, with a preferred embodiment employing piezoelectric materials, to directly drive the spool in a power control servovalve. The achieved control bandwidth is two to five times higher than that achieved by comparably sized valves employing electromagnetic drives. The invention also provides for a package that is more compact and lightweight than servovalves of comparable size.
The invention utilizes the high force, high frequency response characteristics of a smart material element and applies this actuation capability directly to the servovalve spool and without an intermediate pilot fluid system. An embodiment of the invention comprises a valve body with a valve spool having a longitudinal axis, a smart material element, and a mechanical lever. The mechanical lever is mounted to a pivot support means and is positioned relative to the smart material element and valve spool such that expansive motion induced into the smart material element enforces motion on the first end of the mechanical lever which motion is thereby amplified by the lever at the second end of the lever. The second end drives the end of the valve spool thus causing the valve spool to shift along its longitudinal axis an amplified distance commensurate with the expansion and contraction of the smart material element.
The positioning of the smart material element relative to the valve spool is maintained in a compact form such that the mechanical lever is kept as small and stiff as possible to minimize the compliance and mass of the lever and thus maintain the high bandwidth control capability of the smart material element.
The invention also serves as a method for effecting high bandwidth control of a servovalve. An embodiment of the method is comprised of inducing a shape change into a smart material element, mechanically amplifying a component of motion of the shape change of the smart material element, applying the mechanically amplified component of motion directly to the end of the valve spool such that the spool is caused to shift to a different valve spool position, and varying the induced shape change in the smart material in a controlled manner such that the valve spool is forced to shift between valve positions in a commensurate controlled manner.

Piezoelectrically actuated single-stage servovalve


Methods and compositions are disclosed utilizing hydroxyomeprazole for the treatment of ulcers in humans. Hydroxyomeprazole exhibits a lessened liability toward drug-drug interactions than omeprazole and a more predictable dosing regimen than omeprazole. Hydroxyomeprazole is also useful for the treatment of gastroesophageal reflux and other conditions related to gastric hypersecretion such as Zollinger-Ellison Syndrome.

This invention relates to compositions of matter containing hydroxyomeprazole. The invention also relates to methods of treating and preventing ulcers, treating other conditions related to gastric hypersecretion, and treating psoriasis.
Omeprazole I is an orally active, potent,
irreversible inhibitor of H+,K+-ATPase. It is commercially available in the form of Prilosec(copyright) delayed release capsules from Astra Merck Inc. The compound is one of the class of compounds known as gastric xe2x80x9cproton pumpxe2x80x9d inhibitors. These compounds are weak organic bases which diffuse passively from the plasma into the acid-containing intracellular canaliculi of gastric parietal cells. At the low pH found in the lumen of these canaliculi, the protonated compounds rearrange to form pyridinium sulfenamides, which react with sulfhydryl groups present on the ATPase localized in the membranes lining the intracellular canaliculi. The alkylation of the sulfhydryl inhibits the ability of the enzyme to catalyze the secretion of H+ into the lumen in exchange for K+ ions. This inhibition results in an overall reduction in hydrochloric acid secretion by the parietal cells into the cavity of the stomach, thus increasing intragastric pH. As a consequence of reduced acidity in the stomach, the activity of the proteolytic enzyme pepsin is also markedly decreased. Because the proton pump is the final step in acid production and the compounds of this class combine covalently with the associated H+,K+-ATPase, a profound and prolonged inhibition of gastric acid secretion can be achieved.
Proton pump inhibitors have also been reported as useful in treating psoriasis. [See PCT application WO95/18612]
The Cmax of racemic omeprazole is at about 0.5 to 3.5 hours in humans, and the serum half-life is about 30 to 60 minutes, although this is highly variable, as discussed below. The major metabolites in human serum are 5-hydroxyomeprazole II (referred to as hydroxyomeprazole herein) and omeprazole sulfone III.
The two major primary metabolites, omeprazole sulfone and 5-hydroxyomeprazole, are formed by cytochromes P450 3A (CYP3A) and 2C19 (CYP2C19), respectively. Both metabolites undergo further metabolism to the common metabolite 5-hydroxyomeprazole sulfone via CYP2C19 and CYP3A, respectively. Thus, both CYP enzymes are sequentiallyxe2x80x94but alternativelyxe2x80x94involved in omeprazole metabolism. CYP2C19, the S-mephenytoin hydroxylase, is polymorphically expressed in the human population. The mutant allele constitutes the recessive trait. Homozygous carriers of the mutation completely lack CYP2C19 and are referred to as poor metabolizers (PM""s); persons homozygous and heterozygous for the xe2x80x9cnormalxe2x80x9d allele are extensive metabolizers (EM""s). A hereditary deficiency of the alternative enzyme, CYP3A, has not been demonstrated in the human population.
The individual enantiomers of racemic omeprazole are differentially metabolized by CYP 2C19. (+) Omeprazole is rapidly hydroxylated; (xe2x88x92) is not. The individual enantiomers of racemic omeprazole do not appear to be differentially metabolized by CYP 3A4; both are oxidized to the achiral sulfone at comparable rates. This results in a divergence in serum metabolite concentration profiles between poor metabolizers and extensive metabolizers. The mean 8-hour AUC ratio of (+)-omeprazole/(+)-hydroxyomeprazole is 30 times higher and the 8-hour AUC of omeprazole sulfone is more than 10 times higher in poor metabolizers than are the corresponding parameters in extensive metabolizers.
It would be desirable to find a compound with the advantages of omeprazole which would provide a more predictable dosage regimen in the patient population and that would decrease the chances for drug-drug interactions.
This invention relates to the use of hydroxyomeprazole for treating ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison Syndrome, and other disorders including those that would benefit from an inhibitory action on gastric acid secretion. Hydroxyomeprazole inhibits the H+,K+-ATPase associated with the gastric proton pump and the resulting secretion of gastric acid by parietal cells providing therapy in diseases associated with gastric hyperacidity. The invention also relates to a method of treating psoriasis using hydroxyomeprazole. Hydroxyomeprazole provides a more predictable dosage regimen in the patient population and decreases the chances for drug-drug interactions by avoiding oxidative metabolism for which the cytochrome P450 2C19 enzyme system is required.
The invention also relates to certain pharmaceutical compositions containing hydroxyomeprazole.
The active compound of these compositions and methods is hydroxyomeprazole. The preparation of racemic hydroxyomeprazole has been described by Renberg et al. [Drug Metabolism and Disposition, 17:1, 69-76 (1989)], the disclosure of which is incorporated herein by reference. Chemically, the compound of the invention is 2-[[(5-hydroxymethyl-4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl-[1H]-benzimidazole (II), hereinafter referred to as hydroxyomeprazole. Hydroxyomeprazole is not presently commercially available.
Hydroxyomeprazole possesses a center of asymmetry at the sulfoxide sulfur, giving rise to two enantiomers. Throughout the instant disclosure, when the term is not otherwise modified, hydroxyomeprazole includes the (+) enantiomer, the (xe2x88x92) enantiomer and any mixture of the two. The preparation of the individual enantiomers of the parent, omeprazole, has been described in the literature, but the enantiomers of hydroxyomeprazole have been previously disclosed only as identities assigned to peaks on a chromatogram. The individual enantiomers of hydroxyomeprazole can be obtained by asymmetric oxidation of the thioether precursor and bioreduction of the racemate to eliminate one or the other enantiomer in analogous fashion to the procedure described for lansoprazole in PCT applications WO 9602535 and 9617077; the disclosures of both are incorporated herein by reference. The thioether precursor is available by the method of Renberg (op. cit.).
The literature does not appear to provide any reports of testing in vivo or of the administration of racemic hydroxyomeprazole or either of its enantiomers to human subjects. The inhibitory effects of omeprazole and rac-hydroxyomeprazole on aminopyrine uptake in isolated gastric glands have been reported; the IC50 of racemic omeprazole was 0.48 xcexcM and the IC50 of racemic hydroxyomeprazole was 33 xcexcM. Renberg et al. [Drug Metabolism and Disposition, 17:1, 69-76 (1989)] concluded that the contribution of race-hydroxy-omeprazole to the pharmacological response to treatment with omeprazole in humans was probably insignificant.
It has now been discovered that hydroxyomeprazole is a superior agent for treating ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison Syndrome, psoriasis and other disorders, including those that would benefit from an inhibitory action on H+,K+-ATPase in that it provides this effective treatment while exhibiting fewer or less severe adverse effects than omeprazole, less potential for drug-drug interactions than omeprazole and a more predictable dosing regimen than omeprazole. Adverse effects of omeprazole include hepatocellular neoplasia, gastric carcinoids, headache, diarrhea and skin alterations.
The present invention encompasses a method of treating ulcers, which comprises administering to a human in need of such therapy, an amount of hydroxyomeprazole, or a pharmaceutically acceptable salt thereof, said amount being sufficient to alleviate the symptoms of ulcers.
The present invention also encompasses an oral antiulcer composition for the treatment of a human in need of antiulcer therapy, which comprises a pharmaceutically acceptable carrier for oral administration and a therapeutically effective amount of hydroxyomeprazole, or a pharmaceutically acceptable salt thereof. Preferably the composition is in the form of a tablet or capsule, and the amount of hydroxyomeprazole in the tablet or capsule is preferably about 100-500 mg.
The present invention further encompasses a method of treating gastroesophageal reflux disease and of treating conditions caused by or contributed to by gastric hypersecretion. Conditions associated with hypersecretion in humans may include, but are not limited to, Zollinger-Ellison syndrome.
The present invention further encompasses a method of treating psoriasis.
Utilizing hydroxyomeprazole results in enhanced dosage predictability and an improved therapeutic index. In particular, hydroxyomeprazole exhibits less variation in the patient population between so-called extensive metabolizers and poor metabolizers than does omeprazole.
The term xe2x80x9ctreating ulcersxe2x80x9d as used herein means treating, alleviating or palliating such conditions, and thus providing relief from the symptoms of nausea, heartburn, post-prandial pain, vomiting, and diarrhea.
The term xe2x80x9ca method for treating gastroesophageal reflux diseases in a humanxe2x80x9d as used herein means treating, alleviating or palliating the conditions that result from the backward flow of the stomach contents into the esophagus.
The term xe2x80x9ctreating a condition caused, or contributed to, by gastric hypersecretion in a humanxe2x80x9d as used herein means treating, alleviating or palliating such disorders associated with hypersecretion, thus providing relief from the symptoms of the aforementioned conditions. Zollinger-Ellison Syndrome is among the conditions caused by or contributed to by hypersecretion.
The term xe2x80x9ctreating psoriasisxe2x80x9d as used herein means treating, alleviating or palliating the condition, and thus providing relief from the symptoms of pruritis, epidermal scaling, itching and burning.
The term xe2x80x9coptically purexe2x80x9d as used herein means that the compositions contain at least 90% by weight of one enantiomer and 10% by weight or less of the other. In a more preferred embodiment the term xe2x80x9csubstantially optically purexe2x80x9d means that the composition contains at least 99% by weight of one enantiomer, and 1% or less of the opposite enantiomer. In the most preferred embodiment, the term xe2x80x9csubstantially optically purexe2x80x9d as used herein means that the composition contains greater than 99% by weight of a single enantiomer. These percentages are based upon the total amount of hydroxyomeprazole in the composition.
The magnitude of a prophylactic or therapeutic dose of hydroxyomeprazole in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration. The dose and perhaps the dose frequency will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose range for hydroxy-omeprazole for the conditions described herein is from about 50 mg to about 1500 mg in single or divided doses. Preferably a daily dose range should be about 500 mg to about 1000 mg in single or divided doses. In managing the patient, the therapy should be initiated at a lower dose, perhaps at about 50 mg and increased up to about 1000 mg or higher depending on the patient""s global response. It is further recommended that children and patients over 65 years and those with impaired renal or hepatic function, initially receive low doses, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. The terms xe2x80x9can amount sufficient to alleviate or palliate ulcersxe2x80x9d xe2x80x9can amount sufficient to alleviate the symptoms of gastroesophageal refluxxe2x80x9d, xe2x80x9can amount sufficient to alleviate gastric hypersecretionxe2x80x9d and xe2x80x9can amount sufficient to treat psoriasisxe2x80x9d are encompassed by the above-described dosage amounts and dose frequency schedule.
The relative activity, potency and specificity of hydroxyomeprazole both as a gastric antisecretory agent and as a plasma gastrin elevating agent can be determined by a pharmacological study in animals according to the method of Decktor et al. [J. Pharmacol. Exp. Ther. 249, 1-5 (1989)]. The test provides an estimate of relative activity, potency and, through a measure of specificity, an estimate of therapeutic index. Fasted rats, implanted with a gastric cannula, receive single oral or parenteral doses of (+) hydroxyomeprazole, (xe2x88x92) hydroxyomeprazole or racemate, 1 hour before collection of gastric juice over a four hour period. Acid output and pH are then determined on each sample. Dose response evaluations are performed with each compound to determine the lowest dose which inhibits acid output by at least 95% and maintains gastric pH above 7.0. Plasma gastrin levels are then determined in a second group of rats treated with the doses selected in the first series of tests. Blood samples are taken for analyses over the five hour period after dosing, and both peak level as well as area-under-the-curve analyses of the gastrin responses are made. These responses are then analyzed statistically using Student""s xe2x80x9ctxe2x80x9d test to assess whether equivalent antisecretory doses show differences in gastrin responses.
Any suitable route of administration may be employed for providing the patient with an effective dosage of hydroxyomeprazole. Rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, and like forms of administration are possible, but oral administration is preferred. Oral dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, and the like.
The pharmaceutical compositions of the present invention comprise hydroxyomeprazole as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
The terms xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d or xe2x80x9ca pharmaceutically acceptable salt thereofxe2x80x9d refer to salts prepared from pharmaceutically acceptable non-toxic bases. Since the compound of the present invention is a weak acid and is unstable at low pH, salts may be prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Suitable pharmaceutically acceptable base addition salts for the compound of the present invention include metallic salts of aluminum, calcium, lithium, magnesium, potassium, sodium, titanium and zinc or organic salts made from lysine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choiine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Sodium salts are preferred.
The compositions of the present invention include suspensions, solutions, elixirs and solid dosage forms. Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like are suitable in the case of oral solid preparations (such as powders, capsules, and tablets), and oral solid preparations are preferred over the oral liquid preparations. It has been found that the inclusion of mannitol and of basic salts of calcium and magnesium in the compositions allows the preparation of tablets and capsules that retain good stability. Because of the acid instability of hydroxyomeprazole, it is usually advantageous to coat oral solid dosage forms with an enteric or delayed-release coating. This may be accomplished by standard aqueous or nonaqueous techniques. Oral dosage forms suitable for hydroxyomeprazole are described in U.S. Pat. No. 5,035,899 and in PCT applications WO96/01624, WO97/12580 and WO97/25030, the disclosures of which are incorporated herein by reference.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release formulations, which are well known in the art. Compositions suitable for rectal administration are described in European Application 645140, the disclosure of which is incorporated herein by reference.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet or capsule contains about 100 mg to 500 mg of the active ingredient.
An enteric coating, such as the polyacrylate Eudragit L(copyright) and Eudragit S(copyright) series, is applied by spray coating the tablets, preferably with an aqueous dispersion of the coating polymer. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the excipients or to the final weight of the tablet. Oral, as well as parenteral, sustained release drug delivery systems are well known to those skilled in the art, and general methods of achieving sustained release of orally or parenterally administered drugs are found in any standard pharmacy school textbook, for example Remington: The Science and Practice of Pharmacy. Chapter 94 of the 19th edition of Remington entitled xe2x80x9cSustained-Release Drug Delivery Systemsxe2x80x9d describes the more common types of oral and parenteral sustained-release dosage forms (pages 1660-1675.) The disclosure is incorporated herein by reference.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier. for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
The invention is further defined by reference to the following examples describing in detail the preparation of the compositions of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the invention.


An organic solvent based cosmetic remover composition gelled to a viscosity of 25 to 500,000 centipoise with a synthetic metal silicate gelling agent.

The invention is in the field of cosmetic compositions used for removing polymeric films from keratinous surfaces.
Most often, it is desirable that cosmetic compositions applied to keratinous surfaces form some type of film on the keratinous surface. The tenacity and durability of the film formed depends on the type of cosmetic that is applied. For example, in nail enamel compositions, it is most desirable that the nail enamel film permanently adhere to the nail and be durable enough to withstand normal wear for at least several days. On the other hand, cosmetics such as eye or face makeup are generally worn for only one day and removed at the end of the day prior to retiring. Most cosmetic compositions that form a film on a keratinous surface contain at least one type of synthetic or natural film forming polymer which facilitates adhesion to the keratinous surface, and provides durability of the film while on the surface.
Cosmetic films can be removed from keratinous surfaces in a variety of ways. Certain cosmetics such as foundations, eye makeup, and the like can simply be washed off with water, or removed with commercially available makeup removers. Removal of cosmetic films formed by certain transfer resistant lipsticks or nail enamel may necessitate remover compositions containing certain types of solvents that are strong enough to dissolve the film formed by the cosmetic composition.
There are a number of problems with current commercial cosmetic remover compositions. The first is that most of such compositions are in the liquid form. Thus, if applied to the keratinous surface too generously, the remover may drip onto neighboring areas of the body, or onto clothing or household objects. This is not only uncomfortable for the user, but it may cause staining of clothing or objects as well. The second problem with commercially available removers is that they may be drying to the keratinous surface due to the presence of the inorganic solvents. The organic solvents, in turn, are necessary to effect removal of the cosmetic composition from the keratinous surface.
In order to eliminate the problem with dripping, various types of cosmetic remover compositions have been prepared in the gel form. These removers have a higher viscosity than the liquid removers, and will not readily drip off of the keratinous surface to which they are applied, or migrate from the area to which they are applied to other neighboring areas. Gelled remover compositions are not difficult to make, and a number of them are still commercially available. However, the problem still remains that these remover compositions do not exhibit any improvements in conditioning or moisturizing the keratinous surface. Rather, they tend to be the same drying formulas as the liquid formulas.
There is a need for cosmetic remover compositions which are gelled to a viscosity that permit easy application and minimizes dripping or migration, and at the same time provides superior moisturization and conditioning to the keratinous surface.
It is an object of the invention to provide cosmetic remover compositions in the gel form.
It is a further object of the invention to provide cosmetic remover compositions in the gel form and which also provide moisturizing and conditioning benefit to the keratinous surface.
It is a further object of the invention to provide a cosmetic remover composition gelled with a synthetic metal silicate gelling agent.
The invention is directed to an organic solvent based cosmetic remover composition gelled to a viscosity of 25 to 500,000 centipoise with a synthetic metal silicate gelling agent.
The invention is also directed to a method for gelling an organic solvent based cosmetic remover composition to a viscosity of 25 to 500,000 centipoise with a synthetic metal silicate gelling agent.
All percentages mentioned herein are percentages by weight unless otherwise indicated.
The term xe2x80x9ccosmetic remover compositionxe2x80x9d means a composition that, when applied to a keratinous surface having a cosmetic film thereon, is capable of removing the cosmetic film from the keratinous surface in reasonable period of time. A reasonable period of time is the amount of time consumers traditionally allot for such makeup removal, and can range from fractions of a second up to one minute, possibly longer. The cosmetic remover composition may be applied by brushing onto the keratinous surface with a brush impregnated with the remover composition, or by impregnating an applicator with the remover composition and rubbing the keratinous surface having the cosmetic film thereon, or by dipping the keratinous surface into a remover composition one or more time to remove the film. An example of the latter type of removal is a container having the remover composition therein, in the form of a hard gel that is capable of exerting sufficient pressure on the keratinous surface dipped therein such that the film will be removed.
The term xe2x80x9corganic solvent basedxe2x80x9d means that the cosmetic remover composition contains sufficient organic solvent to efficaciously remove the cosmetic film from the keratinous surface. The organic solvent based cosmetic remover composition may by anhydrous, or aqueous based.
The cosmetic remover composition remover composition comprises at least one organic solvent capable of removing the cosmetic film on the keratinous surface, and at least one synthetic metal silicate gelling agent as further described herein.
The Organic Solvent
The cosmetic remover composition is organic solvent based. Of the organic solvents used in the composition, at least one organic solvent should be capable of removing, either by itself, or when combined with other organic solvents, the cosmetic film on the keratinous surface. Suitable organic solvents are non-aqueous, and include hydrocarbons, organic alcohols, ketones, esters of organic alcohols, glycols, ethers, and the like. Preferably, one or more of the organic solvents are volatile, e.g. have a vapor pressure of at least 2 mm. of mercury at 20xc2x0 C. The claimed composition comprises 0.5 to 95%, preferably 1-85%, more preferably 15-60% by weight of the total composition of one or more organic solvents.
Organic alcohols are suitable for use as the organic solvent in the claimed compositions, and include aliphatic or aromatic mono-, di- or trifunctional alcohols. Preferably, the organic alcohols are C1-8 aliphatic mono- or difunctional alcohols, or C1-8 alkoxy alkyl alcohlols, or aromatic alcohols, such as ethanol, isopropanol, butanol, butylene glycol, ethylene glycol, propylene glycol, benzyl alcohol, butoxyethanol, butoxypropanol, butoxyisopropanol, and the like.
Suitable ketones are aliphatic or aromatic ketones having the general formula Rxe2x80x94COxe2x80x94R wherein each R is independently a C1-8 alkyl, or benzyl, or Rxe2x80x94COxe2x80x94R forms a lactone. Examples of such ketones include acetone, propanone butyrolactone, methyl ethyl ketone, diacetone alcohol, and the like.
Suitable esters of organic alcohols include C1-8 aliphatic or aromatic acids, reacted with C1-8 aliphatic mono-, or difunctional, or aromatic, alcohols. Examples of such alcohols include butyl acetate, ethyl acetate, benzyl acetate, benzyl benzoate, benzyl glycol, butylene glycol propionate, butyl octanol, dibutyl adipate, dibutyl oxalate, dibutyl phthalate, dibutyl sebacate, isobutyl acetate, isoamyl acetate, and the like.
Suitable ethers include those of the formula Rxe2x80x94Oxe2x80x94R wherein each R is independently a C1-10 alkyl, a C1-10 alkoxy alkyl, or benzyl. Suitable examples of such ethers include methyl ether, ethyl ether, propyl ether, benzyl glycol, butoxydiglycol, and the like.
Also suitable are various straight or branched chain paraffinic hydrocarbons having 5 to 20 carbon atoms, more preferably 8-20 carbon atoms. Suitable hydrocarbons include pentane, hexane, heptane, decane, dodecane, tetradecane, tridecane, and C8-20 isoparaffins as disclosed in U.S. Pat. Nos. 3,439,088 and 3,818,105, both of which are hereby incorporated by reference. Preferred volatile paraffinic hydrocarbons have a molecular weight of 70-225, preferably 160 to 190 and a boiling point range of 30 to 320, preferably 60-260 degrees C., and a viscosity of less than 10 cs. at 25 degrees C. Such paraffinic hydrocarbons are available from EXXON under the ISOPARS trademark, and from the Permethyl Corporation. Suitable C12 isoparaffins are manufactured by Permethyl Corporation under the tradename Permethyl 99A. Another C12 isoparaffin (isododecane) is distributed by Presperse under the tradename Permethyl 99A. Various C16 isoparaffins commercially available, such as isohexadecane (having the tradename Permethyl R), are also suitable.
Preferred organic solvents depend on the type of remover composition that is being formulated. In nail enamel remover compositions, the preferred organic solvents are esters or ketones, either alone or in combination with C1-4 aliphatic or aromatic alcohols. Preferred organic solvents for use in compositions for removal of makeup from the eyes and face are paraffinic hydrocarbons.
The claimed compositions contain a synthetic metal silicate gelling agent in an amount sufficient to gel the remover composition to a viscosity ranging from 25 to 500,000 centipoise at room temperature (25xc2x0 C.). The term xe2x80x9csyntheticxe2x80x9d means that the gelling agent is synthesized from simple silicates and salts in the presence of mineralizing agents, in contrast to natural metal silicates such as bentonite or hectorite which are obtained from clay and tend to be heavily contaminated with other minerals such as dolomite or quartz, which are not easily removed. The term xe2x80x9cgelling agentxe2x80x9d means that the synthetic metal silicate is capable of gelling a polar material into a gel or sol state. A gel is a high viscosity colloidal dispersion and a sol is a low viscosity colloidal dispersion. Preferred metal silicates for use in the claimed composition, at a concentration of 2% w/w in water, provide a Bingham Yield Value ranging from 25 to 250 dynes/cm2. The term xe2x80x9cBingham Yield Valuexe2x80x9d is defined as the shear stress which has to be exceeded before the rate of shear shows a linear relationship to the shear stress. The Bingham Yield Value is generally determined by obtaining a flow curve relating the shear stress to the rate of shear, and then extrapolating the straight line section of the curve to the shear stress axis, with the intercept being the Bingham Yield Value. The metal silicate gelling agent is preferably an alkali metal silicate or alkaline earth metal silicate gelling agent. Suitable alkali metals or alkaline earth metals include sodium, potassium, magnesium, lithium, and the like. The most desirable synthetic metal silicates for use in the claimed compositions will provide remover compositions where the undisturbed viscosity of the remover composition is greater than the disturbed viscosity. In other words, when these compositions are subjected to shear stress the viscosity will decrease temporarily, and if no further shear stress is applied, the gel will reform and the composition will return to its original viscosity. Preferably the undisturbed viscosity at room temperature (25xc2x0 C.) is 10 to 90% greater than the disturbed viscosity. For example, the disturbed viscosity of one embodiment of the claimed composition may be 20,000 centipoise and the undisturbed viscosity 50,000 centipoise. In this example, the undisturbed viscosity of the composition is 71% greater than the disturbed viscosity.
The synthetic metal silicates may be made in a variety of ways well known in the art. For example, Granquist and Pollack, in Clays and Clay Minerals, on pages 150-169, teach the manufacture of synthetic metal silicates by combining pre-washed gels of magnesium hydroxide and silica and redispersing in water to form a suspension. Then lithium hydroxide, lithium fluoride, or sodium hydroxide are added to the suspension, which is then treated hydrothermally by refluxing with stirring until a product having a crystal structure similar to hectorite is formed.
Another synthetic metal silicate suitable for use in the claimed composition may be synthesized as described in U.S. Pat. No. 3,586,478, which is hereby incorporated by reference. The ""478 patent teaches the formation of synthetic metal silicates by forming an aqueous slurry of a water soluble magnesium salt, sodium silicate, sodium carbonate and/or sodium hydroxide, and a source of lithium or fluoride ions which may be lithium fluoride or a lithium compound in conjunction with hydrofluoric acid, fluosilicic acid, sodium silico fluoride, or sodium fluoride. The aqueous slurry is formed by co-precipitation by combining the magnesium salt, the acid sodium silicate, and the sodium carbonate or hydroxide with heating and agitation in an aqueous medium which contains the source of fluoride ions. Synthetic metal silicates prepared in this manner have the general formula:
(Si8Mg6-xLix.O20.(OH)4-yFy). x(xe2x88x92).x/nMa(xe2x88x92)
wherein:
x is between 0 and 6
y is 1 to 4; and
M is a cation which is preferably sodium or potassium.
Also suitable are synthetic metal silicates made as described in British Patent No. 1,213,122. These metal silicates are made by combining a water soluble magnesium salt with an aqueous alkaline solution of one or more sodium compounds in the presence of the dissolved silicon material, while maintaining the pH from 8 to 12.5, and thereafter exposing the mixture to high temperature and pressure. The resulting solid and liquid phases are then separated to obtain the synthetic metal silicate. Such metal silicates preferably have the general formula:
[SiaMgaLibH4+cO 24](12-2a-b-c)xe2x88x92.M(12-2a-b-c)+
wherein:
M is sodium, lithium, or an organic cation
the value of a, b, and c are such that
a less than 6; b greater than 0; c greater than 0;
and
b+c less than 2; +/xe2x88x92(a+b+cxe2x88x926) less than 2
or
a less than 6; b=0; +/xe2x88x92c less than 2.
Particularly preferred for use in the claimed compositions are synthetic metal silicates as described in British Patent No. 1,432,770. These metal silicates are made by forming an aqueous suspension of magnesium carbonate, and forming a silica precipiate in the aqueous suspension. The mixture is maintained in the wet state and subjected to a hydrothermal treatment by heating in an aqueous medium in the presence of the remaining constituents of the magnesium silicate until crystal growth occurs. The resulting crystalline products are then separated. The resulting synthetic metal silicate has the following general formula:
[Si8(MgaLibHc)O20(OH)4-yFy]zxe2x88x92 zM+
wherein:
a is 4.95 to 5.7
b is from 0to 1.05
c is from 0 to  less than 2
a+b+c is from  greater than 4 to less than 8
y is from 0to  less than 4
z=12-2a-b-c
M is Na+ or Li
Particularly preferred are synthetic metal silicates sold by LaPorte Industries Limited under the tradename Laponite. These synthetic metal silicates are made by combining salts of sodium, magnesium, and lithium with sodium silicate at controlled rates and temperatures. The amorphous precipitate produced is then partially crystallized at elevated temperatures which, after washing and drying, provides a fine white powder. Suitable Laponites include XLG and XLS, which are free flowing white powders, preferably free of fluoride, having the name of hydrous sodium lithium magnesium silicate.
The claimed composition may contain from about 0.01-20%, preferably 0.1-15%, more preferably 0.5-10% by weight of the total composition of the synthetic metal silicate gelling agent.
Water
Preferred remover compositions comprise water. Suggested amounts of water range from 0.5-95%, preferably 1-85%, more preferably 5-75% by weight of the total composition.
Other Ingredients
It may also be desirable to include other ingredients in the remover compositions including surfactants, emollients, stabilizing agents, and the like.
Suitable surfactants include nonionic, anionic, amphoteric, or zwitterionic surfactants. The surfactant, if present, may range from 0.01-20%, preferably 0.05-15%, more preferably 0.1-15% by weight of the total composition. Preferred are nonionic surfactants, including those produced by the condensation of alkylene oxide groups with a hydrophobic compound. Examples of nonionic surfactants are:
(a) Long chain dialkyl sulfoxides containing one short chain alkyl or hydroxy alkyl radical of from about 1 to 3 carbon atoms and one long hydrophobic chain which may be an alkyl, alkenyl, hydroxyalkyl, or ketoalkyl radical containing from about 8 to 20 carbon atoms, from 0 to 10 ethylene oxide moieties, and 0 or 1 glyceryl moiety.
(b) Polysorbates, such as sucrose esters of fatty acids. Examples of such materials include sucrose cocoate, sucrose behenate, and so on.
(c) Polyethylene oxide condensates of alkyl phenols, for example the condensation products of alkyl phenols having an alkyl group of 6 to 20 carbon atoms with ethylene oxide being present in amounts of about 10 to 60 moles of ethylene oxide per mole of alkyl phenol.
(d) Condensation products of ethylene oxide with the reaction product of propylene oxide and ethylene diamine.
(e) Condensation products of aliphatic alcohols having 8 to 18 carbon atoms with ethylene oxide, for example a coconut alcohol/ethylene oxide condensate having 10 to 30 moles of ethylene oxide per mole of coconut alcohol, the coconut alcohol fraction having 10 to 14 carbon atoms. Particularly preferred are polyethylene glycol ethers of methyl glucose, also referred to as methyl gluceth.
(f) Long chain tertiary amine oxides such as those corresponding to the general formula:
R1R2R3NO
wherein R1 contains an alkyl, alkenyl or monohydroxyalkyl radical ranging from about 8 to 18 carbon atoms in length, from 0 to about 10 ethylene oxide moieties, and from 0 to about 1 glyceryl moiety and R2 and R3 are each alkyl or monohydroxyalkyl groups containing from about 1 to about 3 carbon atoms.
(g) Long chain tertiary phosphine oxides corresponding to the general formula:
RR1R2PO
wherein R contains an alkyl, alkenyl, or monohydroxyalkyl radical having 8 to 18 carbon atoms, from 0-10 ethylene oxide moieties and 0 or 1 glyceryl moiety, and R2 and R3 are each alkyl or monohydroxyalkyl group containing from about 1 to 3 carbon atoms.
(h) Polyethylene glycol (PEG) glyceryl fatty esters, having the formula
RC(O)OCH2CH(OH)CH2(OCH2CH2)nOH
wherein n is 5-200 and RC(O)xe2x80x94is a hydrocarbylcarbonyl group wherein R is preferably an aliphatic radical having 7 to 19 carbon atoms.
(i) C10-18 alkyl(C1-6)polyhydroxy fatty acid amides such as C12-18 methylglucamides, N-alkoxy polyhydroxy fatty acid amides, N-propyl through N-hexyl C12-18 glucamides and so on.
(j) Alkyl polysaccharides having a hydrophobic group of 6 to 30, preferably 10, carbon atoms and a polysaccharide group such as glucose, galactose, etc. Suitable alkyl polysaccharides are octyl, nonydecyl, undecyldodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl, di-, tri-, tetra-, penta-, and hexaglucosides, galactosides, lactosides, glucoses, fructosides, fructoses, and so on.
It may also be desirable to incorporate one or more secondary gelling agents in the composition. Suitable gelling agents may be present at 0.001-20%, preferably 0.005-15%, more preferably 0.01-10% by weight of the total composition.
Suitable gelling agents include acrylic polymers, carboxylated salts, propylene carbonate, and so on.
The term xe2x80x9ccarboxylated salt gelling agentxe2x80x9d means the gelling agent is formed by the reaction of a salt with a compound containing at least one carboxylic acid group. Preferably the carboxylic acid-containing compound is a fatty acid and the carboxylated salt gelling agent is the salt of a water insoluble fatty acid and a base. While the fatty acid used to make the carboxylated salt gelling agent is generally water insoluble, the resulting gelling agent may be water soluble or water insoluble. Preferably, the carboxylated salt gelling agent in accordance with this invention is water soluble, i.e. after the water insoluble fatty acid is reacted with the metallic cation (such as sodium) the gelling agent is water soluble. Suitable fatty acids used to make the gelling agent are C12-40 straight or branched chain, saturated or unsaturated fatty acids. Suitable fatty acids include lauric, myristic, palmitic, stearic, oleic, linoleic, linolenic, behenic, caprylic, stearic, and so on. In addition, oils containing fatty acid mixtures, such as palm kernel, olive, tallow, peanut, rapeseed, and the like may be used as the fatty acid component. Preferred are C16-22 fatty acids such as lauric, stearic, or behenic. Most preferred is where the fatty acid is stearic acid.
A variety of cations may be used. Generally the type of cation selected will determine whether the resulting gelling agent is water soluble or water insoluble. Generally cations such as sodium, potassium, or low molecular weight amines or alkanolamines will provide water soluble gelling agents. Suitable amines are ammonia and derivatives thereof Suitable alkanolamines include mono- di- and triethanolamines.
Examples of gelling agents which may be used in the compositions of the invention are sodium, potassium, aluminum, magnesium, or calcium salts of stearic, behenic, caprylic, tallowic, tallic, cocoic, or lauric acids, and so on. Preferably the gelling agent used in the compositions of the invention are water soluble salts of fatty acids and sodium, and in particular sodium stearate.
Polysaccharides are also suitable secondary gelling agents. Examples of polysaccharides include galactans, galactomannans, glucomannans, polyuronic acids, and the like. Preferably the polysaccharides exhibit pendant hydrophilic groups, which are preferably sulfate. Suitable galactans are agar, agarose, kappa carageenan, iota carageenan, lambda carageenan, and the like. Examples of suitable galactomannans are locust bean gum and guar; examples of glucans are cellulose, starch, dextrans, pullulan, beta 1,3-glucans, chitin, xanthan, tamarind and the like; examples of glucomannans are konjac; examples of polyuronic acids are algin, alginates, pectins; examples of heteropolysaccharides are gellan, welan, gum arabic, karaya gum, okra gum, aloe gum, gum tragacanth, gum ghatti quinceseed gum, psyllium, starch arabinogalactan and so on. Also suitable are dextran sulfate, heparin, pectin, sodium alginate, cellulose gum, cellulose acetate priopionate carboxylate, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like. The polysaccharides may be derivatized with various groups such as sulfate, carboxylate, hydroxyl, and so on.
Also suitable for use as the gelling agent are PPC""s formed by the reaction of the anionic polysaccharides mentioned above and a protein. The term xe2x80x9cproteinxe2x80x9d when used in accordance with this invention means a peptide chain having at least two amino acid residues, preferably at least five, and more preferably more than one hundred amino acid residues. Most preferably the protein is a high molecular weight polypeptide which is preferably water soluble, and may be natural, plant (vegetable) proteins, or animal derived proteins, as well as synthetic proteins provided they react with the hydrophilic pendant groups on the polysaccharide to form a PPC. The isoelectric point of the protein used to make the PPC is not critical. Examples of natural proteins include albumen, amylase, amyloglucosidase, arginine/lysine polypeptide, casein, catalase, collagen, crystalline, cytochrome C, deoxyribonuclease, elastin, fibronectin, gelatin, gliadin, glucose oxidase, glycoproteins, hexyldecyl ester of hydrolyzed collagen, human placental protein, human placental enzymes, iodized corn protein, keratin, lactoferrin, lactoglobulin, lactoperoxidase, lipase, milk protein, hyristoyl glycine/histidine/lysin polypeptide, nisin, oxido reductase, pancreatin, papin, pepsin, placental protein, protease, saccharomyces polypeptides, serum albumin, serum protein, silk, sodium stearoyl lactalbumin, soluble proteoglycan, soybean palmitate, soy, egg, peanut, cottonseed, sunflower, pea, whey, fish, seafood, subtilisin, superoxide dismutase, sutilains, sweet almond protein, urease, wheat germ protein, wheat protein, whey protein, zein, hydrolyzed vegetable protein, and the like. Preferred is casein which is a mixture of phosphoproteins obtained from cow""s milk; and milk protein which is a mixture of proteins obtained from cow""s milk.
Also suitable as gelling agents are anionic polymers, such as acrylic polymers which are generally sold in the form of aqueous solutions or dispersions. Such acrylic polymers may be homo- or copolymers of monomers such as acrylamide, methacrylamide, acrylic acid, methacrylic acid, C1-22 alkyl acrylates, C1-22 alkyl methacrylates, and so on. The monomers may also be copolymerized with other organic compounds such as alkoxylated fatty alcohols. The resulting polymers may also be cross-linked with cross-linking agents such as the allyl ether of sucrose, pentaerythritol, or propylene. Preferred are copolymers of monomers A or B, wherein A is selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof, and B is selected from the group consisting of a C1-22 alkyl acrylate, a C1-22 alky methacrylate, and mixtures thereof Preferably, the A monomer comprises one or more of acrylic acid or methacrylic acid, and the B monomer is selected from the group consisting of a C1-10, most preferably C1-4 alkyl acrylate, a C1-10, most preferably C1-4 alkyl methacrylate, and mixtures thereof Most preferably the B monomer is one or more of methyl or ethyl acrylate or methacrylate. Most preferably, the acrylic copolymer is supplied in an aqueous solution having a solids content ranging from about 10-60%, preferably 20-50%, more preferably 25-45% by weight of the polymer, with the remainder water. The composition of the acrylic copolymer may contain from about 0.1-99 parts of the A monomer, and about 0.1-99 parts of the B monomer. One example of such an acrylic polymer solution is sold by Seppic, Inc., under the tradename Capigel, in particular, Capigel 98, which is a white liquid having a pH of 2 to 4, a solids content of about 29-31, a density of 1.04 to 1.08, and a viscosity of 700-1000 millipascal seconds at 25xc2x0 C.
Other types of polymers may contain A and B monomers which are copolymerized with alkoxylated fatty alcohols having the general formula:
Rxe2x80x94(CH2CH2O)nH
wherein n is 1-500.
Examples of polymers containing A and B monomers polymerized with alkoxylated alcohols include acrylates/steareth-50 acrylate copolymer, acrylates/steareth-20 methacrylate copolymer, and the like. Such polymers are sold under the tradenames Acrysol and Acculyn by Rohm and Haas, and Antil by Goldschmidt.
Also suitable are homo- or copolymers of monomers A and B above, which are cross-linked with various cross-linking agents such as the allyl ether of sucrose, the allyl ether of pentaerythritol, or the allyl ether of propylene. Examples of these polymers include those sold under the CTFA name Carbomer, which is defined as a homopolymer of acrylic acid crosslinked with an allyl ether of sucrose, pentaerythritol, or propylene. Carbomers are sold under the tradename Carbopol by B. F. Goodrich or Tego by Goldschmidt, as well as other vendors.
Particularly preferred as a secondary gelling agent in the claimed compositions is propylene carbonate.


A temperature control device including a temperature sensor which senses a temperature at a specified location within the refrigeration apparatus. The temperature control device has first flow valve that is operable to selectively increase or decrease the flow of refrigerant in response to the temperature sensed by the sensor. In addition, the device has a second flow valve that is operable to selectively increase or decrease hot gas flow in response to the temperature sensed by the sensor. The temperature control device also contains a controller which controls the above mentioned valves in response to the temperature sensed by the temperature sensor.

The present invention relates generally to temperature control in a refrigeration device. More particularly, the present invention relates to a back-up temperature control mechanism that allows a refrigerator or incubator to remain within a preset temperature range should the primary temperature control mechanism fail.
Electronic control packages have been developed for providing precise temperature control in refrigeration equipment including, e.g., ultra low freezers, incubators, and walk-in freezers. In refrigeration equipment, particularly in laboratory refrigeration equipment, the desire is to accurately maintain the temperature within the chamber below a desired set point. The selected set point would ordinarily be selected as the temperature necessary to preserve test samples from degradation. In refrigeration equipment, cooling is performed by absorbing heat within an enclosed chamber into a cooled refrigerant gas and transferring that heat into ambient air outside of the refrigeration device.
Similarly, incubators also exchange heat within a chamber to outside ambient air utilizing the same methods. Unlike refrigeration equipment, which operates to keep the chamber below a set point temperature, incubators must maintain the temperatures between lower and upper set point temperatures. While refrigeration equipment is typically used to preserve items placed in the chamber, incubators are used to conduct experiments in controlled temperature environments.
Thus, while refrigeration equipment only requires apparatus for cooling the inner chamber relative to ambient air temperature, an incubator must be able to both cool and heat the chamber to remain within the desired temperature range. In order to maintain highly precise temperature control in the foregoing devices, microprocessor control devices have been employed and are now standard on laboratory equipment.
While an electronic component on these controllers only fails occasionally, the damage an end-user of the refrigerator can suffer from such failure can be quite severe because products stored or being tested in the refrigeration equipment can be damaged or the tests compromised. Thus, the effects can be devastating when an electronic component fails, subjecting the stored products to unintended temperature conditions.
There is therefore a need for a temperature control mechanism which allows for backup control when a primary controller fails. More particularly, there is a need for a mechanism for refrigeration equipment to cycle within an acceptable temperature range automatically on failure of the primary temperature control thereby reducing the chances of property loss if the primary controller fails.
The foregoing needs are met, to a great extent, by the present invention where, in one aspect, a temperature control device is provided having a temperature sensor which senses temperature at a specified location within the refrigeration apparatus. The temperature control device has a first flow valve that is operable to selectively increase or decrease the flow of refrigerant in response to the temperature sensed by the sensor. In addition, the device has a second flow valve that is operable to selectively increase or decrease hot gas flow in response to the temperature sensed by the sensor. The temperature control device also contains a controller which controls the above mentioned valves in response to the temperature sensed by the temperature sensor.
In accordance with another aspect of the invention, the device includes a means for sensing a temperature at certain location of an incubation system. The device has a means for increasing or decreasing refrigerant flow in a first flow path in response to the temperature sensed by the sensing means. In addition, the device provides a means for increasing or decreasing hot gas flow in a second flow path in response to the temperature sensed by the sensing means. The device also provides a means for controlling the valves in response to the temperature in response to the temperature sensed by the sensing means.
In accordance with yet another aspect of the present invention, a method for providing back-up temperature control is provided by first maintaining the temperature inside a chamber within a selected range utilizing a first controller. Second, back-up temperature control is provided by sensing the temperature inside a chamber by utilizing a second temperature controller. Third, back-up temperature control is provided by measuring the the time duration after the compressor cycles on and a first valve is open. Fourth, back-up temperature control is provided by turning the first valve off after a predetermined time has passed and turning a second valve on. And finally, back-up temperature control is provided by cycling the compressor off when the temperature in the chamber is outside the selected range of the first controller and reaches a minimum temperature set point of the second temperature controller.
There has thus been outlined, rather broadly, the more important features of the invention in order that the detailed description thereof that follows may be better appreciated. There are, of course, additional features of the invention that will be described below and which will form the subject matter of the claims appended hereto.
In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein, as well as the abstract, are for the purpose of description and should not be regarded as limiting.
As such, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention.

Method and apparatus for temperature control in a refrigeration device