A method for treating the disease state in mammals caused by mammalian cells involved in the inflammatory response is disclosed. Mammalian cells participating in the inflammatory response are contacted with an inflammatory response mediator which reduces the undesired inflammatory response and is an antioxidant. The inflammatory response mediator may further provide a cellular energy source and be a building block in the cellular synthesis of other cellular components. Compositions for reducing and treating undesired inflammatory response are also disclosed.

1. Field of the Invention
This invention pertains to therapeutic methods of preventing and treating the damage and resulting disease state in mammals caused by mammalian cells involved in the inflammatory response resulting in undesired respiratory bursting, production of enzymes and cellular signaling agents in mammalian cells. This invention also pertains to compositions used in the therapeutic methods.
2. Description of the Prior Art
Reactive oxygen species are generated by cells in response to inter alia aerobic metabolism, catabolism of drugs, toxins and other xenobiotics, ultraviolet and x-ray radiation and the respiratory burst of phagocytic cells (such as white blood cells) to kill invading bacteria and in response to foreign bodies. Hydrogen peroxide, for example, is produced during respiration of most living organisms especially by stressed and living cells.
These active oxygen species can injure cells. An important example of such damage is lipid peroxidation which involves the oxidative degradation of unsaturated lipids. Lipid peroxidation is highly detrimental to membrane structure and function and can cause numerous cytopathological effects. Cells defend against lipid peroxidation by producing radical scavengers such as superoxide dismutase, catalase, and peroxidase. Injured cells have a decreased ability to produce radical scavengers. Excess hydrogen peroxide can react with pyrimidines to open the 5, 6-double bond. This reaction inhibits the ability of pyrimidines to hydrogen bond to complementary bases, Hallaender et al. (1971). Such oxidative biochemical injury can result in the loss of cellular membrane integrity, reduced enzyme activity, changes in transport kinetics, changes in membrane lipid content, and leakage of potassium ions, amino acids, and other cellular material.
The production of reactive oxygen intermediates has been suggested to cause many skin, tissue, and organ disorders such as atherosclerosis, arthritis, cytotoxicity, skin inflammation, photoaging, wrinkling, actinic keratosis, tumor formation, cancer, hypertension, Parkinson""s disease, lung disease, and heart disease. The role of active oxygen radicals in promoting tumors has been proposed based on the findings that (a) tumor promoters increase the level of oxygen radicals, (b) many free radical generating systems promote tumors, and (c) certain antioxidants inhibit the biochemical effects of tumor promoters.
In vitro, reactive oxygen intermediates can be generated in cellular culture media by autooxidation and photooxidation of media components. During excision and storage, transplant organs can suffer oxidative injuries which result in thee loss of cellular membrane integrity and shorten the usable life of the organ.
When cells are stressed by oxidative injury, a resuscitation step is necessary to recondition the cells. Antioxidants have been shown to inhibit damage associated with active oxygen species. For example, pyruvate and other alphaketoacids have been reported to react rapidly and stoichiometrically with hydrogen peroxide to protect cells from cytolytic effects, O""Donnell-Tormey et al., J. Exp. Med., 165, pp. 500-514 (1987).
U.S. Pat. No. 5,210,098 issued to Nath discloses a method to arrest or prevent acute kidney failure by administration of a non-toxic pyruvate salt to a patient in need of such treatment. The therapeutic method comprises administration of an amount of pyruvate salt to a patient experiencing, or in danger of, acute renal failure. The pyruvate salt, preferably sodium pyruvate, is preferably dispersed or dissolved in a pharmaceutically acceptable liquid carrier and administered parenterally in an amount effective to arrest or prevent said acute renal failure, thus permitting restoration of normal kidney function. In some cases, the pyruvate may be infused directed into the kidney or into the proximal renal arterial circulation. The method is effective to prevent or counteract acute kidney failure due to a wide variety of causes, including, but not limited to, traumatic injury, including bum injury and obstruction; reperfusion following ischemia, inflammatory glomerulonephritis, and sepis, e.g. due to gram negative bacterial infection.
U.S. Pat. No. 5,296,370, issued to Martin et al., discloses therapeutic compositions for preventing and reducing injury to mammalian cells and increasing the resuscitation rate of injured mammalian cells. In one embodiment, the therapeutic composition comprises (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the resuscitation of injured mammalian cells.
U.S. Pat. No. 5,256,697 issued to Miller et al., discloses a method for orally administering a therapeutically effective amount of pyruvate precursor to a mammal to improve insulin resistance, lower lasting insulin levels and reduce fat gain.
U.S. Pat. Nos. 3,920,835, 3,984,556, and 3,988,470, all issued to Van Scott et al. disclose methods for treating acne, dandruff, and palmar keratosis, respectively, which consist of applying to the affected area a topical composition comprising from about 1% to about 20% of a lower aliphatic compound containing from two to six carbon atoms selected from the group consisting of alpha-hydroxyacids, alpha-ketoacids and esters thereof, and 3-hydroxybutryic acid in a pharmaceutically acceptable carrier. The aliphatic compounds include pyruvic acid and lactic acid.
U.S. Pat. Nos. 4,105,783 and 4,197,316, both issued to Yu et al., disclose a method and composition, respectively, for treating dry skin which consists of applying to the affected area a topical composition comprising from about 1% to about 20% of a compound selected from the group consisting of amides and ammonium salts of alpha-hydroxyacids, beta-hydroxyacids, and alpha-ketoacids in a pharmaceutically acceptable carrier. The compounds include the amides and ammonium salts of pyruvic acid and lactic acid.
U.S. Pat. No. 4,234,599, issued to Van Scott et al., discloses a method for treating actinic and nonactinic skin keratoses which consists of applying to the affected area a topical composition comprising an effective amount of a compound selected from the group consisting of alpha-hydroxyacids, beta-hydroxyacids, and alpha-ketoacids in a pharmaceutically acceptable carrier. The acidic compounds include pyruvic acid and lactic acid.
U.S. Pat. No. 4,294,852, issued to Wildnauer et al., discloses a composition for treating skin which comprises the alpha-hydroxyacids, beta-hydroxyacids, and alpha-ketoacids disclosed above by Van Scott et al. in combination with C3-C8 aliphatic alcohols.
U.S. Pat. No. 4,663,166, issued to Veech, discloses an electrolyte solution which comprises a mixture of L-lactate and pyruvate in a ratio from 20:1 to 1:1, respectively, or a mixture of D-beta-hydroxybutyrate and acetoacetate, in a ratio from 6:1 to 0.5:1, respectively.
Sodium pyruvate has been reported to reduce the number of erosions, ulcers, and hemorrhages on the gastric mucosa in guinea pigs and rats caused by acetylsalicylic acid. The analgesic and antipyretic properties of acetylsalicylic acid were not impaired by sodium pyruvate, Puschmann, Arzneimittelforschung, 33, pp. 410-415 and 415-416 (1983).
Pyruvate has been reported to exert a positive inotropic effect in stunned myocardium, which is a prolonged ventricular dysfunction following brief periods of coronary artery occlusions which does not produce irreversible damage, Mentzer et al., Ann.Surg., 209, pp. 629-633 (1989).
Pyruvate has been reported to produce a relative stabilization of left ventricular pressure and work parameter and to reduce the size of infarctions. Pyruvate improves resumption of spontaneous beating of the heart and restoration of normal rates and pressure development, Bunger et al., J. Mol. Cell. Cardiol., 18, pp. 423-438 (1986), Mochizuki et al., J. Physiol. (Paris), 76, pp. 805-812 (1980), Regitz et al., Cardiovasc, Res., 15 pp. 652-658 (1981), Giannelli et al., Ann.Thorac. Surg., 21 pp. 386-396. (1976).
Sodium pyruvate has been reported to act as an antagonist to cyanide intoxication (presumably through the formation of cyanohydrin) and to protect against the lethal effects of sodium sulfide and to retard the onset and development of functional, morphological, and biochemical measures of acrylamide neuropathy of axons, Schwartz et al., Toxicol. Appl. Pharmacol., 50 pp. 437-442 (1979), Sabri et al., Brain Res., 483, pp. 1-11 (1989)
A chemotherapeutic cure of advanced L1210 leukemia has been reported using sodium pyruvate to restore abnormally deformed red blood cells to normal. The deformed red blood cells prevented adequate drug delivery to tumor cells, Cohen, Cancer Chemother, Pharmacol., 5, pp. 175-179 (1981).
Primary cultures of heterotopic tracheal transplant exposed in vivo to 7, 12-dimethylbenz(a)anthracene were reported to be successfully maintained in enrichment medium supplemented with sodium pyruvate along with cultures of interleukin-2 stimulated peripheral blood lymphocytes, and plasmacytomas and hybridomas, pig embryos, and human blastocysts, Shacter, J. Immunol, Methods, 99, pp. 259-270 (1987), Marchok et al., Cancer Res., 37, pp. 1811-1821 (1977), Davis, J. Reprod. Fertil, Suppl., 33, pp 115-124 (1985), Okamoto et al., No To Shinkei, 38, pp. 593-598 (1986), Cohen et al., J. In Vitro Fert. Embryo Transfer, 2, pp. 59-64 (1985).
U.S. Pat. Nos. 4,158,057, 4,351,835, 4,415,576, and 4,645,764, all issued to Stanko, disclose methods for preventing the accumulation of fat in the liver of a mammal due to the ingestion of alcohol, for controlling weight in a mammal, for inhibiting body fat while increasing protein concentration in a mammal, and for controlling the deposition of body fat in a living being, respectively. The methods comprise administering to the mammal a therapeutic mixture of pyruvate and dihydroxyacetone, and optionally riboflavin. U.S. Pat. No. 4,548,937, issued to Stanko, discloses a method for controlling the weight gain of a mammal which comprises administering to the mammal a therapeutically effective amount of pyruvate, and optionally riboflavin. U.S. Pat. No. 4,812,479, issued to Stanko, discloses a method for controlling the weight gain of a mammal which comprises administering to the mammal a therapeutically effective amount of dihydroxyacetone, and optionally riboflavin and pyruvate.
Rats fed a calcium-oxalate lithogenic diet including sodium pyruvate were reported to develop fewer urinary calculi (stones) than control rats not given sodium pyruvate, Ogawa et al., Hinvokika Kivo, 32, pp. 1341-1347 (1986).
U.S. Pat. No. 4,521,375, issued to Houlsby, discloses a method for sterilizing surfaces which come into contact with living tissue. The method comprises sterilizing the surface with aqueous hydrogen peroxide and then neutralizing the surface with pyruvic acid.
U.S. Pat. No. 4,416,982, issued to Tauda et al., discloses a method for decomposing hydrogen peroxide by reacting the hydrogen peroxide with a phenol or aniline derivative in the presence of peroxidase.
U.S. Pat. No. 4,696,917, issued to Lindstrom et al., discloses an irrigation solution which comprises Eagle""s Minimum Essential Medium with Earle""s salts, chondroitin sulfate, a buffer solution, 2-mercaptoethanol, and a pyruvate. The irrigation solution may optionally contain ascorbic acid and alpha-tocopherol. U.S. Pat. No. 4,725,586, issued to Lindstrom et al., discloses an irrigation solution which comprises a balanced salt solution, chondroitin sulfate, a buffer solution, 2 mercaptoethanol, sodium bicarbonate or dextrose, a pyruvate, a sodium phosphate buffer system, and cystine. The irrigation solution may optionally contain ascorbic acid and gamma-tocopherol.
U.S. Pat. No. 4,847,069, issued to Bissett et al., discloses a photoprotective composition comprising (a) a sorbohydroxamic acid, (b) an anti-inflammatory agent selected from steroidal anti-inflammatory agents and a natural anti-inflammatory agent, and (c) a topical carrier. Fatty acids may be present as an emollient. U.S. Pat. No. 4,847,071, issued to Bissett et al., discloses a photoprotective composition comprising (a) a tocopherol or tocopherol ester radical scavenger, (b) an anti-inflammatory agent selected from steroidal anti-inflammatory agents and a natural anti-inflammatory agent, and (c) a topical carrier. U.S. Pat. No. 4,847,072, issued to Bissett et al., discloses a topical composition comprising not more than 25% tocopherol sorbate in a topical carrier.
The addition of sodium pyruvate to bacterial and yeast systems has been reported to inhibit hydrogen peroxide production, enhance growth, and protect the systems against the toxicity of reactive oxygen intermediates. The optimum ratio of unsaturated to saturated fatty acids contained within chicken fat enhanced membrane repair and reduced cytotoxicity. The antioxidants glutathione and thioglycollate reduced the injury induced by oxygen radical species, Martin, Ph. D. thesis, (1987-89).
While the above therapeutic compositions and methods are reported to inhibit the production of reactive oxygen intermediates, none of the compositions and methods treats the damage and resulting disease state in mammals caused by undesired respiratory bursting, production of enzymes and cellular signaling agents in mammalian cells.
The present invention pertains to a method for treating the disease state in mammals caused by mammalian cells involved in the inflammatory response and compositions useful in the method. The method for treating the disease state in mammals caused by mammalian cells involved in the inflammatory response comprises: contacting the mammalian cells participating in the inflammatory response with an inflammatory mediator; wherein the inflammatory mediator is present in an amount capable of reducing the undesired inflammatory response and is an antioxidant.
The inflammatory mediator in addition to reducing the undesired inflammatory response and being an antioxidant, may further provide a cellular energy source and be a building block in the cellular synthesis of other cellular components. The inflammatory mediator may also increase cellular metabolic rate.
The present invention also pertains to compositions for reducing and treating the disease state in mammals caused by undesired inflammatory response comprising: An inflammatory response mediator; and a carrier composition; wherein the inflammatory response mediator is an antioxidant and capable of reducing undesired inflammatory response in mammalian cells.
The inflammatory response mediators may be used individually, in combination and further in combination with a therapeutic agent such as an antibacterial, antiviral, antifungal, protein, enzyme, antihistamine, hormone, nonsteroidal anti-inflammatory, cytokine, and steroid. A preferred method of administering the inflammatory mediator is by inhalation.
Therapeutic compositions and a method for treating the disease state in mammals caused by mammalian cells involved in the inflammatory response have been discovered. The mammalian cells primarily responsible for the inflammatory response are white blood cells or leucocytes. In a method for treating the disease state in mammals caused by mammalian cells involved in the inflammatory response, mammalian cells are contacted with an inflammatory mediator. The inflammatory mediator is present in an amount capable of reducing the undesired inflammatory response and is an antioxidant.
The inflammatory response, often referred to as respiratory bursting, is the response of defensive mammalian cells primarily white blood cells or leucocytes. These cells normally respond to an injury or invasion of the mammal by releasing a number of active compounds at the injury or invasion site. Among the compounds released are enzymes such as proteases and active oxygen species such as hydrogen peroxide.
A purpose of the respiratory burst is to provide a battery of oxidizing agents in response to a stimulant that can be used by the leucocytes for the destruction of foreign cells, viruses, particulates and some toxins which have been ingested by or are in the vicinity of the leucocyte. The term xe2x80x9crespiratory burstxe2x80x9d refers to a coordinated series of metabolic events that take place when leucocytes are exposed to appropriate stimuli. This group of events underlies all oxygen dependent killings by leucocytes.
The first of these events is the sharp increase in oxygen uptake that occurs upon stimulation of the leucocytes. While oxygen consumption by resting leucocytes varies widely by cell type, all respond to appropriate stimuli with an increase in oxygen uptake.
Stimulation of the leucocyte also causes an increase in glucose oxidation via the hexose monophosphate shunt. The hexose monophosphate shunt is a metabolic pathway in which glucose is oxidized to carbon dioxide and a five carbon sugar, with NADP+ serving as electron acceptor. Activation of the hexose monophosphate shunt therefore means that the oxidation of NADPH to NADP+ increases during the respiratory burst. The respiratory burst produces superoxide and hydrogen peroxide. Oxygen taken up by the respiratory burst is converted to superoxide. Hydrogen peroxide appears to arise during the respiratory burst mainly from the dismutation of superoxide anion.
Oxe2x88x922+Oxe2x88x922+2H+xe2x86x92H2O2+O2
It has been demonstrated by Root and Metcalf and reported in J. Clin. Invest. 60:1266 that 80 percent of the superoxide is converted to hydrogen peroxide, and this dismutation reaction is the only important source of the hydrogen peroxide generated during the burst. Hydrogen peroxide and superoxide are believed to be responsible for the killing by leucocytes.
Many agents, both soluble and particulate, are able to activate the respiratory burst. Particulate activating agents include bacteria, viruses and fungi for internal body organs or areas and bacteria, viruses, fungi, fibers, smoke, dust, ash, pollen, smog and the like for body cavities and organs such as the lungs, skin, digestive and excretory tracks open to the environment. Soluble agents can be toxins, medicinal compounds and soluble excretions of bacteria, fungi and infected mammalian cells and the like.
Activation of the respiratory burst in leucocytes usually follows exposure to the stimulus for less than a minute. Upon stimulation of the respiratory burst, the consumption of oxygen in leucocytes increases by over 100 fold resulting in, among other things, the production of superoxide, peroxide and hydrogen peroxide. The term xe2x80x9cleucocytesxe2x80x9d as used herein includes lymphocytes, phagocytes, macrophages and auxiliary cells.
Usually, after respiratory bursting the stimulant and/or the mechanism of stimulation turns off allowing the leucocyte to return to its normal resting state. When the bursting does not turn off, the inflammatory action of the leucocytes continues unchecked causing a number of disease states. These disease states occur as the compounds produced by the leucocytes attack, injure and kill tissue cells and other leucocytes. It is this failure to turn off the respiratory burst and the resulting injury to surrounding tissue cells, blood cells, other leucocytes and injured cells that produces the disease states treated by the present invention. Undesired inflammatory response occurs when the inflammatory response causes injury to host cells and this injury poses an independent threat to the host. In a preferred embodiment, the therapeutic compositions containing an inflammatory mediator are administered locally to the site of inflammation. In another preferred embodiment, the therapeutic compositions are administered systemically. In yet another preferred embodiment, the therapeutic compositions are administered systemically and locally concomitantly.
In a preferred embodiment, the therapeutic compositions are administered by inhalation. The therapeutic compositions may be first nebulized by any suitable means. The therapeutic compositions may be in liquid or solid form with liquid droplets or particle size being small enough to facilitate access to lung tissue by inhalation.
In another preferred embodiment, a sterile solution of therapeutic agent is nebulized and inhaled by the patient. A therapeutically effective amount of inflammatory medication is inhaled. This may be accomplished in a single inhalation or by repeated inhalations over a period of time typically 1 to 30 minutes. Preferably, inhalation will be complete in less than 20 minutes. Most preferably inhalation will be complete in less than 15 minutes.
The term xe2x80x9cinjured cellxe2x80x9d as used herein means a cell which has some or all of the following: (a) injured membranes so that transport through the membranes is diminished and may result in one or more of the following, an increase in toxins and normal cellular wastes inside the cell and/or a decrease in nutrients and other components necessary for cellular repair inside the cell, (b) an increase in concentration of oxygen radicals inside the cell because of the decreased ability of the cell to produce antioxidants and enzymes, and (c) damaged DNA, RNA and ribosomes which must be repaired or replaced before normal cellular functions can be resumed. Preferably the inflammatory mediator when brought into contact with a mammalian cell provides a cellular energy source and a building block in the cellular synthesis of other cellular components.
The inflammatory response being reduced is at least one of the following: oxygen radical production, peroxide production, cytokine and/or protease production, prostiglandin production, erythema, histamine and interlukin production and like responses known in the art as inflammatory responses.
The preferred inflammatory mediator is at least one compound selected from the group consisting of a pyruvate precursor, pyruvate, a lactate precursor and lactate. A precursor is a substance from which another substance is formed and in this text also includes salts. Preferably the pyruvate is selected from the group consisting of pyruvic acid, lithium pyruvate, sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, and the like and mixtures thereof. Sodium pyruvate is most preferred. Another preferred inflammatory mediator is selected from the group consisting of pyruvyl-glycene, pyruvyl-alanine, pyruvyl-leucine, pyruvyl-valine, pyruvyl-isoleucine, pyruvyl-phenylalanine, pyruvamide, dihydroxyacetone, and propylene glycol.
Preferred salts of the inflammation mediator are salts that do not produce an adverse effect on the mammalian cell when applied as a salt of the inflammation mediator. Typical salts would be the lithium, sodium, potassium, aluminum, magnesium, calcium, zinc, manganese, ammonium and the like and mixtures thereof.
The lactate precursor is preferably selected from the group consisting of lactyl-glycene, lactyl-alanine, lactyl-leucine, lactyl-valine, lactyl-isoleucine, lactyl-phenylalanine, lactamide and the various salts of lactate.
Compositions for reducing and treating the disease state in mammals caused by undesired inflammatory response comprise: an inflammatory response mediator; and a carrier composition.
The carrier composition is selected from the group consisting of tablets, capsules, liquids, isotonic liquids, isotonic media, enteric tablets and capsules, parenterals, topicals, creams, gels, ointments, chewing gums, confections and the like.
The inflammatory mediator is administered in a therapeutically effective amount to reduce the undesired inflammatory response. Preferably from 0.001 to 10 grams per dose. More preferably 0.001 to 1 gram per dose and most preferably 0.001 to 0.25 grams per dose. It is understood that the method of administration and the condition being treated will greatly affect the dose required to achieve the therapeutic effect.
Typical airway diseases treatable by the present compositions and method include but are not limited to bronchial asthma, acute bronchitis, emphysema, chronic obstructive emphysema, centrilobular emphysema, panacinar emphysema, chronic obstructive bronchitis, reactive airway disease, cystic fibrosis, bronchiectasis, acquired bronchiectasis, kartaagener""s syndrome, atelectasis, acute atelectasis, chronic atelectasis, pneumonia, essential thrombocytopenia, legionnaires disease, psittacosis, fibrogenic dust disease, diseases due to organic dust, diseases due to irritant gases and chemicals, hypersensitivity diseases of the lung, idiopathic infiltrative diseases of the lungs and the like. Particular disease states to be treated are emphysema and asthma.
The inflammatory mediator of the present invention may be administered prior to, after and/or with other therapeutic agents. Typical therapeutic agents are antibacterials, antivirals, antifungals, antihistamines, proteins, enzymes, hormones, nonsteroidal anti-inflammatories, cytokines, steroids, and the like.
Obviously, numerous modifications and variations of the present invention are possible in the light of the above teachings and the invention is not limited to the example herein. It is therefore understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Method and composition for treating mammalian disease caused by inflammatory response


A high efficiency switching regulator for maintaining a constant d.c. voltage is described. An efficiency improvement of better than 20 percent is realized by use of an alternate low impedance current source for supplying base current to the control transistor of a switching regulator.

This invention relates to the voltage regulator art. Specifically, apparatus is provided for improving the efficiency of a switch mode or switching regulator.
Voltage regulator circuits have been developed for maintaining a constant d.c. voltage supplied to a changing load. Ideally, the voltage regulator should maintain a constant output d.c. voltage for a varying input voltage and a varying load.
Regulator circuits which utilize a series transistor connected between a load and the source of unregulated voltage are well known in the art. A reference voltage is continuously compared with the load voltage and the series transistor is controlled to supply more current when the load voltage is less than the reference voltage. As the load voltage approaches the reference voltage, the series transistor delivers less current.
The series transistor dissipates considerable energy while regulating the load voltage. To reduce this energy consumption, it is possible to operate the series transistor in a switching mode. A switching mode regulator is described in a publication by Motorola Semiconductor Products Inc., No. CER-108, entitled "An Inexpensive Switch Mode Power Supply." The series transistor is forced into full saturation when the load voltage is below a reference voltage, and turned off when the load voltage is substantially equal to the reference voltage. By operating the transistor either fully saturated or turned completely off, the energy consumption of the series regulator transistor is reduced.
The series transistor requires appreciable base current in either type of regulator. The base current is usually supplied by bias resistors. Energy consumption in the bias resistors may be as high as 30 percent of the energy delivered to the load. In order to reduce the amount of energy dissipated by the bias resistors, thereby improving the efficiency of the regulator circuit, an alternate low impedance path for supplying base current is desirable.


A personal care product that includes a personal care composition disposed in a collapsible bag at least partially surrounded by an elastically deformable member and, optionally, an outer container body. The elastic member is constructed of an elastically extensible material that permits the transfer of infrared radiation through at least a portion of the elastic member. Potential energy is generated by stretching the elastically deformable member, which is used to dispense the composition in lieu of a propellant or pump. The container may also include a actuatable valve for dispensing the composition.

Undesirable skin conditions associated with dry skin (e.g., redness, itching, burning, peeling, cracking, scaling, flaking) occur in varying degrees and at various times for most humans. These undesirable skin conditions may be particularly evident in winter. Skin care products formulated with at least one active ingredient to address undesirably dry skin are widely known. For example, occlusives such as petrolatum or silicone oils are widely known to inhibit loss of natural moisture by forming a barrier between the epidermis and the environment. Another approach is the use of keratolytic agents such as alpha-hydroxy acids to enhance the rate of dermal exfoliation. A third approach is the topical application of a humectant such as glycerin to help retain moisture in the skin.
Undesirable skin conditions may also be caused by certain fungi (e.g., Candida albicans), which are known to attack the skin of humans. Fungal infections may be caused by dermatophytes, which are opportunistic organisms, or yeasts, which may occur naturally on the body. Commonly known types of fungal infections include athletes foot; yeast infections of the hair, skin, fingernails and toenails; jock itch; ringworm; and diaper rash. In particular, fungal infections associated with diaper rash may occur more often in infants or young children who are prescribed antibiotics. The antibiotics may alter the balance between the yeast and the "good" bacteria typically present in the intestine of a human by killing the good bacteria. This imbalance may result in an increased yeast concentration in the intestine and, consequently, more yeast being passed out of the body in the stool. The increased amount of yeast being passed out of the body may attack the skin around the anus, perinea, and/or genitals of the child, causing skin irritation.
Still other undesirable skin conditions may be caused by exposure of the skin to certain enzymes. For example, it is believed that fecal proteolytic and lipolytic enzymes, of intestinal and/or pancreatic origin, may play a direct role in causing diaper rash, which can lead to skin irritation and inflammation. Proteases and lipases are classes of enzymes produced by the body to help degrade proteins and fats in the digestive process. When in contact with the skin of a human, these enzymes are capable of causing skin irritation. Typically, proteases and lipases are neutralized prior to passing out of the body. However, sickness or infection may reduce the body's ability to neutralize these enzymes. As a result, these enzymes may retain a significant amount of enzymatic activity when passed out of the body in the stool. In addition, the irritating effects of fecal enzymatic activity toward the skin may be amplified if urine is present and/or if the skin is occluded, which may occur in diaper wearing individuals. Water, and particularly water in the form of urine, is especially effective at diminishing the barrier property of skin, thereby enhancing the susceptibility of skin to fecal enzyme irritation. An alkaline feces pH is a further contributing factor to enhanced enzymatic activity of feces. For example, it is well known that although the feces of breast-fed babies are usually acidic, the feces of bottle-fed and spoon-fed infants are generally alkaline, with a pH ranging from slightly alkaline (pH 7.2-7.5) to very alkaline (pH 8.7 and above). Thus, bottle-fed and spoon-fed infants in particular may have a propensity to develop diaper rash due to pH-enhanced activity of fecal enzymes.
For babies, the occurrence of diaper rash is not uncommon. To address the cause and/or symptoms associated with diaper rash, a caregiver may apply a commercially available rash cream to the diaper rash affected area of a baby's skin. Although commercial diaper rash creams may be effective for addressing the symptoms and/or causes of diaper rash, at least some caregivers may find they are inconvenient to apply, since such creams typically involve rubbing and/or spreading a thick and/or tacky ointment onto the baby's skin. The rubbing and/or spreading action may cause additional frictional irritation to the skin, and the undesirably transfer of the ointment, for example, to one's hands and/or fingers may lead to the inconvenient and additional steps of cleaning one's hands. Thus, at least some caregivers desire a more convenient means to apply personal care compositions to skin.
A variety of containers and delivery systems have been developed for storing, dispensing, and applying skin care compositions to skin or other surfaces (e.g., human skin, animal skin, substrate surfaces). One well known dispensing system is a simple "squeezable" container. That is, a container formed from a flexible material to which a user can apply pressure by squeezing, thereby reducing the internal volume of the container and forcing the contents of the container out through an opening. However, at least some commonly known squeezable containers expel their contents in a manner that may be hard to control. For example, some commonly known lotion dispensers may initially dispense a "blob" of lotion, but eventually stop dispensing, or worse, begin a sort of "splattering" or "sputtering" of lotion, which may result in contamination of clothing or other surfaces. Because of the inexact method of dispensing the skin care composition out of a squeezable container (i.e., applying too much or too little pressure), a user may not dispense the desired amount of lotion. In addition, it may be necessary for a user to spread the skin care composition over the desired area of the body with a hand or finger, resulting in the undesirable contamination of the hands/fingers and/or discomfort to the irritated, highly sensitive areas of the skin.
Aerosol delivery systems have been widely used to deliver a variety of consumer goods, including skin care compositions because they typically "atomize" the composition, which may reduce the need for spreading the composition over the skin (e.g., with a hand or fingers). Aerosol systems typically utilize volatile propellants to push the product out of a container. Aerosol technology has gained favor for being both effective and relatively inexpensive. But the release of traditionally used fluorocarbon and hydrocarbon type propellants into the atmosphere is undesirable due to the actual and perceived negative impacts these chemicals may have on the environment. Another disadvantage is that the aerosol containers are considered pressure vessels, which can necessitate extra safety equipment and procedures during its manufacture. The pressurized containers can also create concern for human injury if problems arise during storage, use, or disposal. And the high internal pressure accompanying many aerosol products may limit the material and geometry options for the container. Yet another disadvantage is that as the amount of product in the container decreases through normal use, the pressure inside the container typically decreases. In at least some instances, when the container no longer has sufficient pressure to expel the stored product, there may still be a useful amount of product remaining in the container. And when the aerosol container is discarded, the remaining product is wasted or may even result in undesirable environmental pollution. Still another disadvantage of aerosol dispensers is that when used to apply a composition to the skin of a user, the composition tends to be expelled at an undesirably cold temperature and may create a feeling of discomfort on the skin of a user.
A pump system is one alternative to aerosols and squeezable containers. Pump systems generally dispense a metered amount of product by actuating a pump. However, different consumers may not all desire the same amount of product for a particular use, and thus difficulty arises in providing a proper metered amount that is satisfactory to all users. For example, a first consumer may need to pump a dispenser two times to dispense the desired amount of product, while another consumer may only require one pump of the same dispenser. And if the desired amount of product is somewhere between pumps, the consumer may become frustrated in attempting to use the pump dispenser. In addition, pump systems typically must be properly oriented to function as intended. For example, some commonly known pump systems will not function properly when the pump is oriented upside-down or even sideways. And some pump systems may dispense undesirably, intermittently, or not at all as the amount of product in the container is depleted. Further, some pump systems may be better than aerosol containers when it comes to expelling the contents the container, but pump systems may still be unable to expel substantially all of their contents. Finally, some nozzles tend to clog if not used for extended periods of time, especially if the skin care composition contains particulate ingredients.
Accordingly, it would be desirable to provide a skin care composition in a non-pump, non-aerosol dispenser. It would also be desirable to provide a skin care composition in a dispenser capable of dispensing substantially all of the skin care composition. It would further be desirable to provide a skin care product that at least reduces the potential for cloggings issues within the dispenser to occur.


A pharmaceutical composition for oral administration contains naloxone-, N-methylnaloxone- and/or N-methylnaltrexone-containing particles which release the active substance depending on the ambient pH. This ensures the liberation of the active substance over the whole gastrointestinal tract. The side effects caused by the use of analgesic opioids, such as constipation, are thus eliminated without reducing the analgesic effect.

The invention relates to new galenic compositions with opioid antagonistic activity and their use in opioid-induced constipation. In particular, the invention relates to pellet, granulate or microtablet compositions comprising the active ingredients naloxone, N-methylnalaxone or N-methylnaltrexone as the active ingredients with opioid antagonistic activity.
Constipation arising through medication with the use of strongly effective analgesics of the morphine type represents a large problem. It is considered as one of the most frequent side effects and is an undesired concomitant symptom particularly in continual therapy. This problem arises during treatment in approximately 85% of the patients given morphine. In contrast to other side effects caused by for example morphine, this is a chronic phenomenom that does not loose intensity during the course of treatment [Saller R., Hellenbrecht D. xe2x80x9cSchmerzen-Therapie in Praxis und Klinikxe2x80x9d, 1st Ed. (1991) Marseille Publishers, Munich]. The paralytic effect of opioids on intestine motility has been known for a long time and is also therapeutically used, for example, in the case of diarrheal illnesses [Manara L., Bianchetti A. xe2x80x9cThe central and peripheral influences of opioids on gastrointestinal propulsionxe2x80x9d, Ann. Rev. Pharmacol. Toxicol. 25, 249-273 (1985)]. Although the mode of action of opioids on intestine motility is not yet completely understood, it is seen in connection with the binding of the opioid to opioid receptors in the intestine. Aside from in the brain, these opioid receptors are also to be found at high density in the gastrointestinal tract above all [Manara L., Bianchetti A. xe2x80x9cThe central and peripheral influences of opioids on gastrointestinal propulsionxe2x80x9d, Ann. Rev. Pharmacol. Toxicol. 25, 249-273 (1985)].
In a series of pharmacological experiments, it could be demonstrated that opioids (morphine was mostly chosen as a model substance) have a direct effect on the smooth musculature of the intestine and, thus, muscle tonicity in intestine segments increases. The enhancement of segmental tonicity leads to a significant prolongation of gastrointestinal passage time with simultaneous decrease of the propulsive motility of the intestine [Cameron J. C. xe2x80x9cConstipation related to narcotic therapyxe2x80x9d, Cancer Nurs. 15, 372-377 (1992)].
The aim of a therapy is to neutralize this peripheral side effect of morphine and related compounds because opioid-induced constipation can be very painful and finally endangers the success of treatment [Glare P., Lickiss J. N. M. xe2x80x9cUnrecognized constipation in patients with advanced cancer: a recipe for therapeutic disasterxe2x80x9d, J. Pain Symptom Manage. 7, 369-371 (1992)]. A little more than half of the patients who suffer from this side effect can be sufficiently taken care of with customary laxatives and thickening agents. For the rest of the patients, satisfactory treatment possibilities are still lacking.
Since it is assumed in opiod-induced constipation that the true effect proceeds directly and locally over the entire intestine through the occupation of opioid receptors, this effect should be able to be neutralized through the use of opioid antagonists. However, the use of opioid antagonists only makes sense when the antagonistic effect on the intestine is limited and the central pain-relieving effect is not neutralized. Therefore, only a few opioid antagonists such as for example naloxone, N-methylnalaxone or N-methylnaltrexone are considered which have a peripheral effect and not an effect in the CNS under certain conditions.
Naloxone is a pure opioid antagonist which is customarily intravenously applied as an antidote in the case of opioid poisoning. After oral administration, naloxone is quickly and completely resorbed. Since the substance is subject to a very pronounced first-pass metabolism, only small amounts of the unaltered substance are systemically available. The predominant portion of the applied substance is present in the blood in the form of the metabolites naloxone-3-glucuronide, xcex2-naloxol-3-glucuronide and xcex2-naloxol which are not effective or only weakly effective [Vollmer K. O. xe2x80x9cPharmakokinetische Grundlagen des Valoron-N-Prinzipsxe2x80x9d, Fortsch. Med. 106, 593-596 (1988)]. As a result of this pharmakinetic property, naloxone in a suitable dose is an ideal candidate for relief of opioid-induced constipation: in the intestine, it is present as an active substance and can thus neutralize the paralytic effect of the opioid on the gastrointestinal tract and, after reabsorption, it is largely metabolized and rendered ineffective with the first liver passage. Thus, the pain-relieving effect of the opioids is not adversely affected.
In various small clinical trials, it could be demonstrated that opioid constipation could be partially neutralized by the oral administration of naloxone: in two studies on healthy probands, Basilisco et al. examined the influence of loperamide, a peripherally effective opioid used in diarrheal illnesses, on the gastrointestinal passage time. They demonstrated that naloxone when intravenously applied (40 xcexcg/kg/hr. in 3 hr) [Basilisco G., Bozzani A., Camboni G., Recchia M., Quatrini M., Conte D., Penagini R., Bianchi P. A. xe2x80x9cEffect of loperamide and naloxone on mouth-to-caecum transit time evaluated by lactulose hydrogen breath testxe2x80x9d, Gut 26, 700-703 (1985)] and after oral administration of relatively high doses of 16 or 32 mg [Basilisco G., Camboni G., Bozzani A., Paravicini M., Bianchi P. A. xe2x80x9cOral naloxone antagonizes loperamide-induced delay of orocecal transitxe2x80x9d, Dig. Dis. Sci. 32, 829-832 (1987)] could neutralize the constipating effect of loperamide.
Culpepper-Morgan et al. report a pilot study in which three patients with opioid-induced constipation were treated with orally applied naloxone. After doses of up to 16 mg, two of the three patients responded to the treatment (neutralisation of constipation). With the other patient, constipation could not be neutralized even with a increase in dose of up to 24 mg naloxone (within 3 hours). Plasma level determinations showed that dose-dependent maximal naloxone concentrations up to 7.9 ng/ml were measured. At doses from 14 mg, the non-responder showed clear withdrawal symptoms which points to an antagonization of the central opioid effect [Culpepper-Morgan J. A., Inturrisci C. E., Portenoy R. K., Foley K., Houde R. W., Marsh F., Kreek M. J. xe2x80x9cTreatment of opioid-induced constipation with oral naxolone: A pilot studyxe2x80x9d, Clin. Pharmacol. Ther. 52, 90-95 (1992)].
Sykes report a study with 12 patients who were administered with oral naloxone at different doses. The naloxone dose was oriented on the daily opioid dose. Naloxone was given in doses of 0.5%, 1%, 2%, 5%, 10%, 20%, and 40% with respect to the opioid dose. No effect was determinable up to 10% naloxone dose. A neutralization of constipation was first reported at the very high dose range (20% to 40%) The absolute naloxone doses which were administered could amount to up to 72 mg naloxone [Sykes N. P. xe2x80x9cOral naloxone in opioid-associated constipationxe2x80x9d, The Lancet 337, 1475 (1991)].
Robinson et al. report a study on 12 patients with opioid-induced constipation in which naloxone was also orally administered. The maximally administered dose was 12 mg naloxone. An effect on the gastrointestinal motility or withdrawal symptoms was not determinable in any of the treated patients [Robinson B. A., Johansson L., Shaw J. xe2x80x9cOral naloxone in opioid-associated constipationxe2x80x9d, The Lancet 338, 581-582 (1991)].
It is striking that in the cited studies, the results turn out very differently and, above all, naloxone is effective when it is applied in high doses. In this dose range, withdrawal symptoms also already arise in individual patients. The active ingredient is released quickly and unmodified in customary, simple compositions (for example, capsules or drops). When using these simple compositions, naloxone is quickly and completely resorbed in the upper part of the gastrointestinal tract. Undesired side effects can arise through the resulting, relatively high blood concentrations. Therapeutical applications of naloxone compositions of this type are described in EP 0 103 636 (A1) and EP 0 352 361 (A1) for example.
However, since the paralysis concerns the entire gastrointestinal tract and not only the duodenum and upper part of the small intestine, the problem of opioid-induced constipation cannot be solved with a composition of this type (for example drops).
DE 4325465 (A1) proposes a combination preparation of an opioid and an opioid antagonist for oral administration, wherein the opioid is released in a retarded manner and, in contrast, the opioid antagonist is quickly released, i.e. with low or no retardation. With respect to the portion of naloxone, this preparation corresponds to a non-modified, quick-releasing composition with the above mentioned disadvantages. Namely, this path increases the danger of an undesired systemic naloxone effect whereby the pain-relieving effect of the opioid is neutralized again. Therefore, using the teaching of DE 4325465 (A1), a complete elimination of these side effects cannot be attained and/or withdrawal symptoms can further occur in patients at the chosen dose ranges.
Correspondingly, the invention has the object of providing an oral, galenic composition with opioid antagonistic activity that, as a result of pharmaceutical-technological properties, is capable of neutralizing opioid-induced constipation without leading thereby to significant systemic availability of naloxone and thus antagonizing the opioid effect in the CNS.
The invention is based on the recognition that an effective antagonization of the opioid effect on the upper and lower parts of the gastrointestinal tract with avoidance of the systemic antagonization of the opioid effect can only then take place when the active ingredient is released in a modified manner over the entire digestive tract. In this connection, the control of the release occurs site-specifically over the various ambient pHs in the respective stomach and/or intestine sections whereby this does not concern a retardation in the sense of a delayed release. Here, when constipation is already present, the danger exists that the intestine passage of the composition is delayed and the active ingredient is prematurely released into the upper sections of the digestive tract whereas the lower sections are not given medical aid.
The above problem is solved by an orally administrable pharmaceutical composition comprising naloxone, N-methylnalaxone and/or N-methylnaltrexone, or a pharmaceutically acceptable salt thereof, as an active ingredient, wherein the release of the active ingredient is achieved over the entire digestive tract by particles contained in the composition which release the active ingredient initially and as a function of the ambient pH. The following embodiments on naloxone apply in the same manner for N-methylnalaxone, N-methylnaltrexone, pharmaceutically acceptable salts of these compounds and mixtures thereof.
Preferred embodiments of the invention are given in the dependent claims.
The naloxone composition according to the invention is distinguished by a targeted and controlled release of active ingredient as uniformly as possible over the entire gastrointestinal tract, i.e. from stomach to colon, wherein a quick release of active ingredient occurs locally in the individual sections of the digestive tract. Since, in contrast to time-dependent, controlled releasing systems, the release of active ingredient is not controlled by the delayed release, but instead, over the varying pH conditions in the digestive tract, the opioid-induced constipation and the delayed gastrointestinal transit of the active ingredient carrier associated therewith (pellets or others) does not lead to an uncontrolled release of the medicament in intestine sections in which it should not be released. Hereby, the composition according to the invention results in the advantage that a smaller single dose can be employed.
In a preferred embodiment, the particles containing active ingredient are provided with a coating that is soluble as a function of the ambient pH. For a coating of this type, customary film-forming substances with a solubility differing as a function of ambient pH can be used. The acryl polymers of the Eudragit(copyright) series known and used in galenics, especially Eudragit(copyright)L100-55, Eudragit(copyright)L-100 and Eudragit(copyright)S100 (obtainable from Rxc3x6hm Pharma GmbH, Weiterstadt, Germany) are preferred. The desired release pH can be adjusted in a targeted manner by suitable mixing of these substances and/or the active ingredient particles coated with these substances.
The possible decrease of the systemic load and the applied dose via the principle of xe2x80x9cdrug targetingxe2x80x9d is a further advantage. As a mono-preparation, the medicament according to the invention additionally allows the use of the most varied opioids for constipation, however, it can also be employed as a combination preparation with a certain opioids, especially morphin, or one or more substances of the morphine type. A selection of such opioids comprises for example codeine, dihydrocodeine, hydromorphone, levomethadone, oxycodone, pethidine and propoxyphene and/or salts thereof. The dosage of the opioid depends on age, sex and the seriousness of the illness of the patients and can be adjusted by the attending physician based on his expert knowledge.
Preferred pharmaceutical medicaments contain naloxone-containing particles (pellets, microtablets or granules) with different lacquer coatings. The particles should preferably be designed such that they pass the pylorus substantially independent of the motility of the digestive tract. For this, a maximal size of approximately 2 mm is favorable. Typically, the pellets have a diameter of approximately 1 mm; the describe microtablets one of approximately 2 mm. The average particle size of the granulate is smaller than approximately 1 mm, preferably approximately 300 to approximately 600 xcexcm. The lacquers on the particles differ by their different solubility characteristics. The solubility of the lacquers and the release of the medicament associated therewith depend on the local pH value of the digestive tract. A mixture of different particles with different release behaviours takes advantage of the strongly varying pH conditions in the digestive tract (stomach approximate pH 1.2, colon approximate pH 7.0).
Preferably, the pharmaceutical composition according to the invention contains at least two types of particles which each release the active ingredient at a different ambient pH. Since opioid-induced constipation in humans occurs to approximately 50% as a result of a delayed gastric emptying and to 25% through the weakened propulsive peristalsis in the small and large intestine regions respectively[Manara L., Bianchetti A. xe2x80x9cThe central and peripheral influence of opioids on gastrointestinal propulsionxe2x80x9d, Ann. Rev. Pharmacol. Toxicol. 25, 249-273 (1985)], an initial release of a certain amount of active ingredient is recommended as soon as the composition arrives in the stomach. For this purpose, the first type of particles can be designed such that the active ingredient is already released at the ambient pH of the stomach. The second particle type then releases the active ingredient at the ambient pH of the lower intestinal tract, i.e. a pH of approximately 7.0. In practice, the first type of particles can already release the active ingredient in a pH independent manner upon contact with an aequeous medium. This initial release can be achieved by providing the first type of particles with a coating comprising methylhydroxypropyl cellulose, and optionally polyethylene glycol (for example Macrogol(copyright) 6000; average molecular weight 6000), as an adjuvant which is soluble in aqueous medium independent of the pH value.
In a preferred embodiment, the ratio of the particles of the first type to the particles of the second type is 1:10 to 10:1, more preferably approximately 1:1. Additionally, further types of particles can be present which release the active ingredient by an ambient pH of approximately 5.5 to 6.5.
In a further preferred embodiment, the pharmaceutical composition comprises a first type of particles which release the active ingredient upon contact with an aqueous medium in a pH independent manner and a second or more types of particles which release the active ingredient at an ambient pH of approximately 5.5 to 7.0.
Thus, in the finished medicament (for example, hard gelatine capsules) a mixture of laminated particles is present which releases the active ingredient in a controlled and modified manner in the stomach, upper and lower small intestine and in the colon. The composition according to the invention can be administered in order to treat an opioid-induced constipation which already exists. However, it can also be given precautionarily in order to prevent from the outset the occurence of constipation with an opioid analgesic treatment.

Galenic composition containing opioid antagonists


The invention relates to a fixing device for orthopedic applications, in which at least one coupling member is mounted in the connecting rod of, or the guiding rod for, the clamping members, intended for receiving orthopedic pins, which coupling member can be brought into a rigid or a flexible coupling position. Further, preferably it has been provided for, that in the flexible coupling position, the flexibility can be adjusted across a certain range.

The invention relates to a fixing device for orthopedic applications, substantially comprising an elongated connecting rod or guiding rod, with at least two clamping members intended for clamping orthopedic pins being adjustably secured to, or being slidably mounted on said rod, and further comprising means for securing said clamping members in relation to said rod.
Such fixing devices to be mounted externally are employed for enabling fixation of adjacent bone portions or bones at both sides of a joint in relation to each other. These devices are known in a number of embodiments, e.g. with an at least partly telescopic fastening rod having at its ends the clamping members or a guiding rod onto which said clamping members have been slidably mounted. For this last-mentioned embodiment, see e.g. NL-A-1007426 in the name of applicant.
When such fixing devices are mounted across a joint, e.g. across a wrist joint at a fracture of or near said wrist joint, this will provide the most stable situation for having the fracture heal properly. At the same time, the tendons and muscles engaging the relevant joint and the area close to it will be completely immobilized, which has the result that after the time required for healing of the fracture, generally, the joint has become completely stuck and it will often take months of physiotherapy to get the joint to move properly again.
According the aspect of the invention, in this existing method of treatment, an essential improvement can be achieved if a fixing device can also temporarily offer a possibility of movement within a certain limited range in relation to the fixing position. Due to this, it will become possible, after initial healing of the fracture, to start a treatment program in which one has a patient carry out small movements of the joint one time or a number of times a day during a certain period. In this way, the joint can be prevented from getting completely stuck and no further treatment or at least no extensive treatment will be required after the fracture has healed.
Accordingly, according to the invention it is provided for, that the connecting rod or guiding rod consists of at least two parts, a coupling member having been mounted between said parts and adjusting means having been provided by which the coupling member can be brought into a rigid coupling position or a flexible coupling position. There, the coupling member is designed in such a way that in the flexible coupling position, the parts located at both sides of the coupling member can only be changed in position across a predetermined maximum range in relation to each other. Through this, it is prevented that the healing fracture can get loaded too heavily through an excessive freedom of movement of the joint concerned.
Although one coupling member can suffice, it is preferred to mount two coupling members spaced apart on the fixing device. This has the advantage, that the fixing device, which will always be at some distance from a joint, will be more able to follow the movement of the joint within the permitted flexible range of the coupling members.
According to a further elaboration it is further provided for, that the adjusting means have been executed in such a way that with the coupling member in the flexible coupling position, the flexibility of the coupling can be controlled within a certain range. Then, the flexibility of the coupling member is preferably such, that both a flexure and a change in length is possible, which, on account of the position of the fixing device in relation to the joint concerned, is of great importance. The change in length intended can be both an extension and an reduction. The ability to control the flexibility within a certain range provides the possibility of starting the therapy with very small movements and gradually enlarging them in time, depending on the healing condition of the fracture.
Further, preferably it has been provided for that a coupling member is connected to the connecting rod or guiding rod on at least one side. This provides the possibility of mounting the coupling member(s) at a desired distance from the clamping members in front of the orthopedic pins and/or at a desired mutual distance, with the help of various lengths of connecting or guiding rod.
According to a preferred embodiment, it is provided for, that a coupling member substantially comprises a connecting part being provided with at least one helical cutout across at least a part of its length, said cut-out extending to the axis of the connecting part or a recess in the connecting part, made at the level of said axis, the adjusting means being in the shape of a retaining sleeve to be mounted across the connecting part.
According to a further elaboration, it has further been provided for, that threading is mounted on the outside of the connecting part and that the retaining sleeve is a threaded sleeve. For the type of thread to be mounted, there are a number of possibilities, such as e.g. a thread having a smaller pitch than the helical cut-out, a left- or right-hand thread or a thread incorporating the helical cut-out, such as trapezium thread.

Fixing device for orthopedic applications


A highchair has a horizontally adjustable tray. It includes: (a) a pair of supports on opposed sides of the highchair each having a plurality of studs on an inside surface thereof; (b) a tray movably coupled between the supports including two underlying engagement members, each of the apertures having an elastic projection projected above the aperture; and (c) an actuator slidably attached to an undersurface of the tray including two vertical members each having a plurality of wedge members corresponding in position to the apertures of the engagement member and one or more elastic elements each having one end biased against the undersurface of the tray and the other end biased against the actuator. The projected elastic projections are structured to restrict the movements of the wedge members so as to effect the locking of the actuator to the tray, and the wedge members are structured to be able to move pass the retracted elastic projections to effect a disengagement of the actuator from the tray. In one embodiment, each of the supports also includes a tube disposed on a leg of the highchair and a plurality of studs releasably coupled to the highchair.

1. Field of Invention
The present invention relates to a highchair and more particularly to a highchair with horizontally adjustable tray with improved characteristics.
2. Related Art
Conventionally, parents buy a highchair to feed an infant. Typically, a highchair comprises a frame with long legs supported on a ground, a seat for supporting the infant, and a tray with food provided thereon.
A number of highchairs with either horizontally adjustable or fixed tray are found in a search such as Taiwanese Patent Publication Nos. 240,409 and 252,424, and 327,300, and U.S. Pat. Nos. 5,087,097, 5,118,161, 5,458,394, 5,507,550, and 5,586,800 wherein above No. 240,409 discloses a highchair with fixed tray and No. 327,300 discloses a highchair with horizontally adjustable tray.
But these are unsatisfactory for the purpose for which the invention is concerned because they are ineffective and/or complex in structure.
It is therefore an object of the present invention to provide a highchair with horizontally adjustable tray. The advantages of the present invention are realized by configuring the highchair to comprise a pair of supports on opposed sides of highchair each having a plurality of elastic projections on the inside; a movable tray coupled between the supports including a tray portion and two beneath engagement members put on the supports each having a plurality of apertures with the elastic projections biased in or out of the apertures for changing the relative positioning of tray with respect to the supports; and a movable actuator in the tray including two vertical members each having a plurality of wedge members corresponding to the apertures of the engagement member and two elastic elements each having one end biased against the inside of tray and the other end biased against actuator, thereby effecting the locking of the actuator to the tray by restricting the movements of wedge members by the projected elastic projections or the disengagement of the actuator from the tray by moving the wedge members to pass over the retracted elastic projections; whereby the tray is capable of positioning in a locked position or moving relative to the supports or even being removed from the supports.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Highchair with horizontally adjustable tray


The invention is a process to recover a high pressure hydrogen rich gas stream from synthesis gas. The synthesis gas is separated into a hydrogen-enriched permeate and a hydrogen-depleted non-permeate by use of a membrane. The permeate experiences a substantial pressure drop of between about 500 psi (23.9 KPa) to 700 psi (33.5 kPa) as it passes through the membrane. The pressure of the non-permeate gas is unchanged by the membrane. The non-permeate gas pressure is reduced to between about 200 and about 500 psi for use in a combustion turbine. The hydrogen-rich permeate is compressed to between about 800 and 3000 psi (143.6 kPa) for use in subsequent operations, i.e., for use in hydrotreating of crude oil. The non-permeate gas is expanded in a manner to provide energy which is used to compress the permeate gas.

This invention relates to recovery and utilization of hydrogen gas from synthesis gas.
The production of synthesis gas from the solid and liquid carbonaceous fuels, especially coal, coke, and liquid hydrocarbon feeds, has been utilized for a considerable period of time and has recently undergone significant improvements due to the increased energy demand and the need for clean utilization of otherwise low value carbonaceous material. Synthesis gas may be produced by heating carbonaceous fuels with reactive gases, such as air or oxygen, often in the presence of steam in a gasification reactor to obtain the synthesis gas which is withdrawn from the gasification reactor.
Synthesis gas mixtures comprise carbon monoxide and hydrogen. Hydrogen is a commercially important reactant for hydrogenation reactions. The synthesis gas can also be used to generate power from otherwise environmentally unacceptable fuel sources, and as a source of feed gas for the synthesis of hydrocarbons, oxygen-containing organic compounds or ammonia.
Other materials often found in the synthesis gas include hydrogen sulfide, carbon dioxide, anmmonia, cyanides, and particulates in the form of carbon and trace metals. The extent of the contaminants in the feed is determined by the type of feed and the particular gasification process utilized as well as the operating conditions. In any event, the removal of these contaminants is critical to make gasification a viable process. As the product gas is discharged from the gasifier, it is usually subjected to a cooling and cleaning operation involving a scrubbing technique wherein the gas is introduced into a scrubber and contacted with a water spray which cools the gas and removes particulates and ionic constituents from the synthesis gas. The initially cooled gas may then be treated to desulfurize the gas prior to utilization of the synthesis gas.
When the most desired product is hydrogen, the synthesis gas from the gasifier is advantageously further processed by water-shifting, also called steam reforming, using catalyst to form hydrogen from carbon monoxide as shown below:
H2O+COxe2x86x92H2+CO2
The water shift process, or steam reforming, converts water and carbon monoxide to hydrogen and carbon dioxide. The shift process is described in, for example, U.S. Pat. No. 5,472,986, the disclosure of which is incorporated herein by reference.
The hydrogen gas is often used in subsequent refining processes, particularly hydrotreating. For many applications, especially for hydrotreating hydrocarbons, the hydrogen is required at higher purity than is available in synthesis gas or even water shifted synthesis gas, and at pressures between about 1000 psi (47.9 kPa) and about 3000 psi (143.6 kPa). The shifted or unshifted synthesis gas must therefore be purified to meet product specifications. In addition, the purified gas may need to be further compressed.
Relatively pure hydrogen at high pressure can be obtained from synthesis gas via the pressure swing absorption process. This method is expensive and requires significant capital outlay. What is needed is an efficient and cost effective method of extracting a relatively pure high pressure hydrogen stream from synthesis gas.
The present invention is a process to recover a high pressure hydrogen rich gas stream from synthesis gas. The synthesis gas is provided at a temperature between about 10xc2x0 C. and about 100xc2x0 C. The synthesis gas is passed along a membrane at high pressure, typically between about 800 psi (38.3 kPa) and about 1600 psi (76.6 kPa), more typically between about 800 psi (38.3 kPa) and about 1200 psi (57.5 kPa). A hydrogen enriched gas permeates through the membrane. The permeate experiences a substantial pressure drop of between about 500 psi (23.9 KPa) to 700 psi (33.5 kPa) as it passes through the membrane. The pressure of the hydrogen-depleted non-permeate gas is unchanged by the membrane. The non-permeate gas pressure is advantageously reduced to between about 200 psi (9.58 kpa) and about 500 psi (23.0 kPa) for use in a combustion turbine by expanding the gas in an expander. The hydrogen-rich permeate is advantageously compressed to between about 800 psi (38.3 kPa) and 3000 psi (143.6 kPa) for use in subsequent operations, i.e., for use in hydrotreating of crude oil. The non-permeate gas is advantageously expanded in a manner to provide energy which is used to compress the permeate gas. It is preferred that an expander be directly coupled with a compressor.
The invention involves the integration of oil refining and gasification, and more particularly the integration of solvent deasphalting, gasification, and hydrotreating. A deasphalted oil is typically separated from a heavy crude through solvent extraction. The bottoms from the extraction, the asphaltenes, are low value hydrocarbonaceous material. Such material may be advantageously gasified to generate hydrogen, power, steam, and synthesis gas for chemical production.
The deasphalted oil can easily be broken down into high-value diesel oil in a fluidized catalytic cracking unit. The deasphalted oil generally contains significant quantities of sulfur- and nitrogen-containing compounds. This deasphalted oil may also contain long chain hydrocarbons. To meet environmental regulations and product specifications, as well as to extend the life of the catalyst, the fluidized catalytic cracking unit feed, i.e., the deasphalted oil, is hydrotreated first to remove sulfur components.
Hydrotreating advantageously utilizes hydrogen that is generated by the gasification unit. This invention concerns a new configuration for the integration of gasification and hydrotreating that is more cost effective that conventional hydrotreating processes.
The integration of gasification and hydrotreating employs a process to recover a high pressure hydrogen rich gas stream from synthesis gas. The hydrogen rich gas stream can also be used for many other purposes. A commercially important use is hydrotreating, also called hydrocracking, of liquid hydrocarbons.
Hydrogen is extracted from synthesis gas using a membrane. A membrane allows small molecules like hydrogen to pass through (permeate) while the larger molecules (CO2, CO) do not permeate. Membranes are a cost effective alternative to a pressure swing absorption unit. However, the membranes have two flaws. They make a large non-permeate steam that must be utilized economically for the process to be cost effective. The membranes reduce the pressure of the product hydrogen so it has to be compressed prior to use. For example, the product hydrogen pressure when purified using a membrane is substantially lower than is required by hydrotreaters. Therefore, hydrogen compressors have been added at significant capital and operating cost. This hydrogen so extracted is make-up hydrogen for the hydrotreater. The hydrogen reacts with the hydrocarbon mixture.
As used herein, the term xe2x80x9csynthesis gasxe2x80x9d refers to gases comprising both hydrogen gas and carbon monoxide gas. The mole ratio of hydrogen to carbon monoxide may, but need not necessarily, be about one to one. There are often some inerts in the synthesis gas, particularly nitrogen and carbon dioxide. There are often other contaminants present, such as hydrogen sulfide and COS.
The synthesis gas is prepared by partially burning a hydrocarbonaceous fuel and oxygen in a reactor, often in the presence of steam, in proportions producing a mixture containing carbon monoxide and hydrogen in the reactor.
The term xe2x80x9chydrocarbonaceousxe2x80x9d as used herein to describe various suitable feedstocks is intended to include gaseous, liquid, and solid hydrocarbons, carbonaceous materials, and mixtures thereof. In fact, substantially any combustible carbon-containing organic material, or slurries thereof, may be included within the definition of the term xe2x80x9chydrocarbonaceousxe2x80x9d. Solid, gaseous, and liquid feeds may be mixed and used simultaneously; and these may include paraffinic, olefinic, acetylenic, naphthenic, asphaltic, and aromatic compounds in any proportion. Also included within the definition of the term xe2x80x9chydrocarbonaceousxe2x80x9d are oxygenated hydrocarbonaceous organic materials including carbohydrates, cellulosic materials, aldehydes, organic acids, alcohols, ketones, oxygenated fuel oil, waste liquids and by-products from chemical processes containing oxygenated hydrocarbonaceous organic materials, and mixtures thereof.
The term xe2x80x9cliquid hydrocarbonxe2x80x9d as used herein is intended to include various materials, such as crude oil, petroleum distillates and residue, gasoline, naphtha, kerosene, crude petroleum, asphalt, gas oil, residual oil, tar-sand oil and shale oil, coal derived oil, aromatic hydrocarbons (such as benzene, toluene, xylene fractions), coal tar, cycle gas oil from fluid-catalytic-cracking operations, furfural extract of coker gas oil, and mixtures thereof.
xe2x80x9cGaseous hydrocarbons,xe2x80x9d as used herein to describe suitable-gaseous feedstocks, include methane, ethane, propane, butane, pentane, natural gas, coke-oven gas, refinery gas, acetylene tail gas, ethylene off-gas, and mixtures thereof.
xe2x80x9cSolid hydrocarbon fuels,xe2x80x9d as used herein to describe suitable solid feedstocks, include, coal in the form of anthracite, bituminous, subbituminous; lignite; coke; residue derived from coal liquefaction; peat; oil shale; tar sands; petroleum coke; pitch; particulate carbon (soot or ash); solid carbon-containing waste materials, such as sewage; and mixtures thereof. Certain types of hydrocarbonaceous fuels, in particular coal and petroleum coke, generate high levels of ash and molten slag.
It is often advantageous to mix feeds. One particularly important hydrocarbonaceous fuel is asphaltenes separated by solvent extraction from a heavy crude or other asphaltene-containing liquid hydrocarbon.
The hydrocarbonaceous fuels are reacted with a reactive oxygen-containing gas, such as air, substantially pure oxygen having greater than about 90 mole percent oxygen, or oxygen enriched air having greater than about 21 mole percent oxygen. Substantially pure oxygen is preferred. The partial oxidation of the hydrocarbonaceous material is completed, optionally in the presence of a temperature control moderator such as steam, in a gasification zone to obtain the hot partial oxidation synthesis gas.
The proportion of oxygen to hydrocarbon should be sufficient to avoid by-product soot formation. There can, however, be formation of carbon in small quantities and in a finely divided state such that it does not constitute a by-product and does not adversely affect any processing steps.
Synthesis gas can be manufactured by any partial oxidation method. Typically, the synthesis gas is manufactured in a partial oxidation, or gasification, reactor wherein hydrocarbonaceous fuels are reacted with oxygen to create hydrogen and carbon monoxide. Preferably, the gasification process utilizes substantially pure oxygen with above about 95 mole percent oxygen. The gasification processes are known to the art. See, for example, U.S. Pat. No. 4,099,382 and U.S. Pat. No. 4,178,758, the disclosures of which are incorporated herein by reference.
In the gasification reactor, the hydrocarbonaceous fuel is contacted with a free-oxygen containing gas, optionally in the presence of a temperature moderator. In the reaction zone, the contents will commonly reach temperatures in the range of about 1,700xc2x0 F. (926xc2x0 C.) to 3,000xc2x0 F. (1649xc2x0 C.), and more typically in the range of about 2,000xc2x0 F. (1093xc2x0 C.) to 2,800xc2x0 F. (1537xc2x0 C.). Pressure will typically be in the range of about 1 to about 250 atmospheres, and more typically in the range of about 15 atmospheres (101 Pa) to about 150 atmospheres (25.3 kPa), and even more typically in the range of about 60 atmospheres (6.08 kPa) to about 80 atmospheres (8.12 kPa).
The gas is cooled and washed of contaminants, preferably with energy recovery such as by steam raising and/or steam superheating. There may follow lower grade heat recoveries, as in conventional synthesis gas manufacturing. There may be conventional steps of steam removal and, where appropriate, of composition adjustment.
If hydrogen gas is a desired product, it is advantageous to subject the synthesis gas to steam reforming to increase the relative yield of hydrogen gas. Steam reforming is a process of adding water, or using water contained in the gas, and reacting the resulting gas mixture adiabatically over a steam reforming catalyst. The purpose of steam reforming is to increase the amount of hydrogen in the gas mixture.
The synthesis gas composition of a gasification reaction is typically hydrogen gas at 25 to 45 mole percent; carbon monoxide gas at 40 to 50 mole percent; carbon dioxide gas at 10 to 35 mole percent; and trace contaminants. In a steam reformed synthesis gas a typical composition is hydrogen gas at 35 to 65 mole percent; carbon monoxide gas at 10 to 20 mole percent; carbon dioxide gas at 30 to 60 mole percent; and trace contaminants. These ranges are not absolute, but rather change with the fuel gasified as well as with gasification parameters.
The steam reforming catalyst can be one or more Group VIII metals on a heat resistant support. Conventional random packed ceramic supported catalyst pieces, as used for example in secondary reformers, can be used but, since these apply a significant pressure drop to the gas, it is often advantageous to use a monolithic catalyst having through-passages generally parallel to the direction of reactants flow.
The gas temperature typically is in the range 750xc2x0 C. to 1050xc2x0 C. A preferred shift reaction is a sour shift, where there is almost no methane and the shift reaction is exothermic.
Contaminants in the gas, especially sulfur compounds and acid gases, can be readily removed. The synthesis gas contains hydrogen sulfide (H2S) and COS formed from sulfur in the feed to the gasifier. The COS is shifted in the steam reformer following the same reaction path as carbon monoxide to form hydrogen sulfide and carbon dioxide.
The hydrogen sulfide, an acid gas, is easily removed from the synthesis gas. Convention amine solvents, such as MDEA, can be used to remove the hydrogen sulfide. Physical solvents such as SELEXOL and RECTIXOL can also be used. The physical solvents are typically used because they operate better at high pressure. The synthesis gas is contacted with the solvent in an acid gas removal contactor. Said contactor may be of any type known to the art, including trays or a packed column. Operation of such a acid removal contactor is known in the art.
It is preferred that the design and operation of the shift reactor result in a minimum of pressure drop. The pressure of the synthesis gas is therefore preserved, and the sulfur removal can be accomplished prior to further hydrogen purification steps or utilization of the hydrogen.
In hydrotreating and hydrocracking operations, hydrogen is contacted with hydrocarbons in the presence of a catalyst. The catalyst facilitated the breaking of carbon-carbon, carbon-sulfur, carbon-nitrogen, and carbon-oxygen bonds and the bonding with hydrogen. The purpose of this operation is to increase the value of the hydrocarbon stream by removing sulfur, reducing acidity, and creating shorter hydrocarbon molecules.
Hydrotreating requires a hydrogen-rich gas comprising greater than about 80 mole percent of hydrogen gas.
The synthesis gas or mixed synthesis gas-purge gas stream is therefore separated into a hydrogen-rich gas stream and a hydrogen-depleted gas stream. Membranes are a preferred alternative to a pressure swing absorption unit.
The membrane can be of any type which is preferential for permeation of hydrogen gas over carbon dioxide and carbon monoxide. Many types of membrane materials are known in the art which are highly preferential for diffusion of hydrogen compared to nitrogen. Such membrane materials include those composed of silicon rubber, butyl rubber, polycarbonate, poly(phenylene oxide), nylon 6,6, polystyrenes, polysulfones, polyamides, polyimides, polyethers, polyarylene oxides, polyurethanes, polyesters, and the like. The membrane units may be of any conventional construction, and a hollow fiber type construction is preferred.
The membranes reduce the pressure of the hydrogen-enriched stream so it has to be compressed prior to use. The synthesis gas or mixed gas stream enters the membrane at high pressure, typically between about 800 (38.3 kPa) and about 1600 psi (76.6 kPa), more typically between about 800 psi (38.3 kPa) and about 1200 psi (57.5 kPa). The gas temperature is typically between about 10xc2x0 C. to about 100xc2x0 C., more typically between about 20xc2x0 C. and about 50xc2x0 C. A membrane allows small molecules like hydrogen to pass through (permeate) while the larger molecule (CO2, CO) do not pass through (non-permeate). The permeate experiences a substantial pressure drop of between about 500 psi (23.9 KPa) to 700 psi (33.5 kPa) as it passes through the membrane. The hydrogen-rich permeate is therefor typically at a pressure of from about 100 psi (4.78 kPa) to about 700 psi (33.5 kPa), more typically between about 300 psi (14.3 kPa) to about 600 psi (28.7 kPa). The permeate may contain between about 85 to about 98 mole percent hydrogen gas. The hydrogen rich permeate must be compressed to be used in, for example, a hydrotreater or hydrocracker.
The non-permeate has negligible pressure drop in the membrane unit. The non-permeate gas stream from the membrane contains carbon dioxide, carbon monoxide, and some hydrogen. Other compounds, in particular volatile hydrocarbons and inerts, may also be present. This non-permeate makes a good fuel for combustion turbines. The pressure of this permeate is advantageously reduced prior to burning in a combustion turbine.
An expander/compressor is used to simultaneously increase the hydrogen pressure and to reduce the non-permeate gas pressure. The number of moles of the non-permeate is typically between about one and about five times the number of moles of the permeate. The non-permeate is at high pressure and the pressure should be lowered for eventual use as combustion turbine fuel gas. The combustion turbine requires a pressure of from about 200 psi (9.57 kPa) to about 500 psi (23.9 kPa), more typically from about 300 psi (14.3 kPa) to about 400 psi (19.1 kPa), for its feeds. The hydrogen-rich permeate is at low pressure and the pressure should be increased for eventual use in, for example, a hydrotreater. The hydrogen-rich permeate is usually required at from about 1000 psi (47.8 kPa) to about 3000 psi (143.6 kPa) , more typically from about 1000 psi (47.9 kPa) to about 1500 psi (71.8 kPa). The expander/compressor has an expander in which the non-permeate expands, which directly drives a compressor which compresses the permeate. No motor is required.
The mass flow between the non-permeate expanding through the compressor and the permeate being compressed in the compressor must be controlled. The compressor and expanders may be turbine, pistons, or any other design known to the art. In any event, the mass throughput through the compressor and expander must balance the compression and expansion pressure ratios. There may also be mechanical limitations.
For a turbine compressor/turbine expander, any changes in mass flow there between must not exceed the design of the gas turbine thrust bearing. Under typical designs, there may be a maximum of 10% variation in relative mass flow through the expander side than that flowing through the compressor side. At the same time, it is recognized that the required flow rates may vary by a factor of more than ten, i.e., from about 10 to about 400 million standard cubic feet per day (about 283 to about 11362 million liters per day) for a typical facility. Nevertheless, the relationship between throughput and compression ratios is well understood. It is therefore within the skill of one skilled in the art, with the benefit of this disclosure, to size the expander and compressor system.
The hydrogen-rich permeate may be further compressed as needed to reach the appropriate pressure level required by a given end-use.
If the end-use is as make-up gas for a hydrotreater, then the hydrogen is advantageously mixed with recycled hydrogen from the hydrotreater that has been compressed to the appropriate pressure. Hydrotreating is an exothermic reaction, but the reactants must be preheated to initiate the reaction. During the hydrotreating process, hydrogen sulfide and short chain hydrocarbons such as methane, ethane, propane, butane and pentane are formed. The hydrogen is recycled to the hydrotreater, and a small purge stream is taken. The purge prevents non-condensables such as hydrogen sulfide, methane, and ethane from building up in the process which would inhibit the reaction.
In one embodiment of this invention, the purge gas is advantageously routed to the gasification unit acid gas removal unit. The purge gas is mixed with synthesis gas. There the impurities are removed from the purge gas/synthesis gas mixture. A hydrogen rich permeate is recovered via the membrane separator, is compressed in an expander/compressor, and is recycled back to the hydrotreater.
Membranes are only partially effective at removing hydrogen gas from the synthesis gas stream. This is not considered a detriment. Typically, hydrotreating requires less than one half of the hydrogen gas generated by gasifying hydrocarbons.
The large non-permeate gas stream must be utilized in a commercially viable process. While this non-permeate gas may be burned in boilers or other heat generating processes, this gas is advantageously burned in a combustion turbine. Therefore, the combustible impurities are routed to a pressurized fuel gas system typically used for a combustion turbine.
A combustion turbine advantageously burns the pressurized non-permeate gas from the membrane and generates power from the expansion turbine. A combustion turbine is a particularly effective method of generating power from pressurized fuel gas. The non-permeate gas must have sufficient composition to support combustion in the combustion turbine. This non-permeate gas is a high carbon dioxide, low BTU content gas. This gas may be mixed with other gases, but such other gases may not be available.
The faster burning material in the non-permeate gas stream is hydrogen. A considerable fraction of the heating value of such gas with very low heating value is provided by hydrogen. The fast burning hydrogen elevates the temperature of the flame considerably in relatively little space, whereupon the other combustibles of the low heating value fuel burn properly. Especially when hydrogen has been burned already, and the gas temperature has therefore been increased, the CO present in the non-permeate gas will then burn quickly. It is essential to have high gas temperature to efficiently combust hydrocarbons present. Therefore, the hydrogen percentage in the non permeate must meet the requirements of the combustion turbine supplier, usually between 5 and 25%.
In one embodiment of this invention, at least a fraction of the energy from the combustion turbine is also used to compress the hydrogen-rich permeate.
Upon review of the above disclosure one of ordinary skill in the art should understand that one illustrative embodiment of the present invention includes a process of manufacturing a high pressure hydrogen-enriched gas stream. Such an illustrative process includes: a) providing a synthesis gas, such that the synthesis gas has a pressure between about 800 psi (38.3 kPa) and about 1600 psi (76.6 kPa), and a temperature between about 10xc2x0 C. to about 100xc2x0 C.; b) passing the synthesis gas along a membrane such that a hydrogen-enriched gas permeates through the membrane, thereby creating a hydrogen-depleted non-permeate and a hydrogen-rich permeate at lower pressure, c) expanding the non-permeate, and d) compressing the permeate to between about 800 psi (38.3 kPa) and about 3000 psi (143.6 kPa) , such that the energy for compressing the permeate is obtained from the expansion of the non-permeate.
In practicing the illustrative method it is preferred that the permeate experiences a pressure drop of between about 500 psi (23.9 kPa) to about 700 psi (33.5 kPa) as it permeates through the membrane. Similarly it is preferred that the expanded non-permeate pressure is between about 200 psi (9.58 kpa) and about 500 psi (23.9 kPa).
The process may further include reacting the compressed hydrogen-enriched permeate with a hydrocarbon mixture, preferably under a hydrotreating conditions so as to give a hydrotreated hydrocarbon. The illustrative process may also include gasifying a hydrocarbonaceous fuel to produce the synthesis gas, wherein the hydrocarbonaceous fuel comprises asphaltenes, and wherein gasifying comprises reacting the hydrocarbonaceous fuel with a gas comprising greater than about 90 mole percent oxygen such that synthesis gas is formed. It is preferred that the synthesis gas comprises between about 25 to about 45 mole percent hydrogen, about 40 to about 50 mole percent carbon monoxide, and about 10 to about 35 mole percent carbon dioxide.
One can react the synthesis gas with steam adiabatically over a steam reforming catalyst before passing the synthesis gas along a membrane. In such embodiments of the invention, the steam reformed synthesis gas should comprise between about 35 to about 65 mole percent hydrogen, about 10 to about 20 mole percent carbon monoxide, and about 30 to about 60 mole percent carbon dioxide.
The illustrative process should preferably be carried out utilizing a membrane selected from one or more of silicon rubber, butyl rubber, polycarbonate, poly(phenylene oxide), nylon 6,6, polystyrenes, polysulfones, p6 lyamides, polyimides, polyethers, polyarylene oxides, polyurethanes, and polyesters. Preferably the permeate comprises greater than about 80 mole percent hydrogen and more preferably the permeate comprises between about 85 and about 98 mole percent hydrogen.
The present illustrative process may be carried out such that the permeate pressure prior to compression is between about 100 psi (4.78 kPa) and about 700 psi 33.5 kPa). More preferably the permeate pressure prior to compression is between about 300 psi (14.3 kPa) and about 600 psi (28.7 kPa).
The number of moles of the non-permeate is preferably between about one and about five times the number of moles of the permeate when carrying out the illustrative method. The non-permeate pressure after expansion is preferably between about 200 psi (9.58 kPa) and about 500 psi (23.0 kPa). It is also preferred that the non-permeate be burned in a combustion turbine.
The compression of the permeate and the expansion of the non-permeate takes place in a compressor/expander, wherein the compressor and the expander are linked so that the expansion of the non-permeate provides the energy to compress the permeate. In such an embodiment, the compressor/expander may be two turbines or the compressor may be a turbine or a piston, and the expander may be a turbine or a piston.

Utilization of membranes and expander/compressors in gasification