The invention relates to a polyphenylene ether resin containing residual aliphatic unsaturation as well as composites, blends, and articles made from the polyphenylene ether resin containing residual aliphatic unsaturation. Also included are reaction products between the polyphenylene ether resin containing residual aliphatic unsaturation and other resins and unsaturated resin formulations, e.g., thermosetting polyesters, acrylics, bismaleiimides, silicones, and allylics, and thermoplastics such as polyolefins, styrenics, rubbers, etc.

Polyphenylene ether resins (hereinafter xe2x80x9cPPExe2x80x9d) are commercially attractive materials because of their unique combination of physical, chemical, and electrical properties. Furthermore, the combination of PPE with other resins provides blends that result in additional overall properties such as chemical resistance, high strength, and high flow.
One technical obstacle to the development of such blends is the lack of compatibility between PPE and many resins. This lack of compatibility manifests itself often through very poor physical properties as well as delamination in molded parts. Methods have been developed to improve the PPE compatibility with many resins such as, for example, with polyesters and polyamides. One of the more effective methods involves functionalizing PPE to make functionalized PPE containing moieties such as acid, anhydride, epoxy, orthoester, and the like that are reactive with the other resin in the blend. It is believed that when the functionalized PPE is allowed to react with the other resin that relatively small amounts of copolymer between the resins are formed. The copolymer is believed to be in large part responsible for improved compatibility between the PPE and the other resin. Indications of improved compatibility include resistance to delamination, improved physical properties such as increased tensile and impact properties and a stabilized morphology between the blend component phases under static and/or low shear conditions.
Methods to prepare functionalized PPE have included solution functionalization with an acid halide containing compound, such as trimellitic anhydride acid chloride, to make an endcapped PPE containing at least one reactive moiety such as acid, anhydride, epoxy, orthoester, and the like. This method is rather limited in the variety of functionalized PPE that can be made. Also, the by-products from the capping reaction tend to cause emulsion and/or isolation issues in the solvent precipitation stage of the process.
Another known method to prepare functionalized PPE related to melt functionalization of the PPE in an extruder. This method involved melting and mixing PPE with a functionalizing agent to result in a functionalized PPE. The functionalizing agent is typically a compound containing a carbon-carbon double or triple bond and one of the aforementioned reactive moieties and is believed to react through the unsaturated bond to functionalize the PPE. Additional polymers could be fed into the same extruder or alternatively, the functionalized PPE could be isolated and subsequently used to prepare other compositions. Melt functionalization has issues, such as difficulty in feeding PPE into the extruder due to low bulk density and wide particle size distribution. Moreover, PPE are often powders and require special handling to avoid potential dust explosion.
As explained above, the methods known in the art teach functionalization of the PPE with reactive groups such as acid, anhydride, epoxy, orthoester, and the like. However, for blending PPE with resin systems that involve curing or polymerization reactions, including radical reactions, it would be highly desirable to have a PPE that contained residual aliphatic unsaturation and capped phenolic end groups at the same time. Incorporation of unsaturated species onto the PPE to result in an olefinic functionalized PPE may allow for chemical grafting to occur between the olefinic functionalized PPE and the other unsaturated species that are being polymerized. Moreover, the hydroxyl groups that exist on PPE may interfere with radical polymerization reactions of unsaturated monomers and lead to undesirable low polymerization rates of the unsaturated monomer species.
PPE known in the art typically are of fairly high molecular weight for blending in the melt phase with other polymers and generally have in excess of 50 repeat monomer units, most often in excess of 80 or more repeat monomer units. Consequently, functionalization reactions and isolation methods have been developed for high molecular weight PPE. Although many physical properties, such as tensile properties, are enhanced with the high molecular weight of the PPE in the polymeric blend, in other new resin blend compositions, such as, for example, the polymerization of vinyl-substituted aromatic monomers, the high viscosity of the PPE having more than 50 repeat monomer units is undesirable as it presents difficulty with mixing. Additionally, the overall number of available endgroups available for chemical modification becomes fairly limited as the molecular weight increases.
For blending PPE with resin systems that involve curing or polymerization reactions, including radical reactions, it would be highly desirable from the standpoints of low viscosity for mixing and a high endgroup number for functionalization to have a PPE that contained residual aliphatic unsaturation and that has less than 50 repeat monomer units on average, preferably less than about 35 repeat monomer units on average. It is therefore apparent that a need continues to exist for novel and improved methods to prepare functionalized PPE containing residual aliphatic unsaturation, especially low molecular weight PPE (i.e. PPE having an intrinsic viscosity less than about 0.30 dl/g as measured in chloroform at 30xc2x0 C.).
The needs discussed above have been generally satisfied by the discovery of a process for preparing functionalized PPE containing aliphatic unsaturation. In one embodiment, the process comprises oxidative coupling in a reaction solution at least one monovalent phenol species using an oxygen containing gas and a complex metal catalyst to produce a PPE; and functionalizing the PPE, preferably prior to and/or during at least one isolation step for devolatilization of the reaction solvent, with an unsaturated compound of the formula (I):
wherein R1 is an aliphatic or aromatic residue, for example, xe2x80x94CH2xe2x80x94 but may be multiple xe2x80x94CH2xe2x80x94 groups, e.g., n can vary from 1 to about 10 or more, or alternatively, n may equal zero wherein the formula is an acrylic residue, and wherein each of R2, R3, and R4 are independently hydrogen, alkyl, or aryl, and wherein X is a residue of one of the following formulae (II):
or wherein X is a halogen or a residue of the formula (III):
wherein R7 is an aliphatic or aromatic residue, for example, xe2x80x94CH2xe2x80x94 but may be multiple xe2x80x94CH2xe2x80x94 groups, e.g., m can vary from 1 to about 10 or more, or alternatively, m may equal zero (wherein if n and m both equal zero, the unsaturated compound is an acrylic anhydride), and wherein each R8, R9, and R10 are independently hydrogen, alkyl, or aryl. In a preferred embodiment, the unsaturated compound is of the formula (IV):
wherein each of n, R1, R2, R3, and R4 are as previously described. In an especially preferred embodiment, the unsaturated compound is of the formula (V):
The description that follows provides further details regarding various embodiments of the invention.
One embodiment of this invention provides for a process for the preparation of functionalized PPE containing aliphatic unsaturation, preferably having an intrinsic viscosity between about 0.08 dl/g and 0.60 dl/g, more preferably between about 0.10 dl/g and about 0.30 dl/g, by oxidative coupling at least one monovalent phenol species, preferably at least a portion of which have substitution in at least the two ortho positions and hydrogen or halogen in the para position, using an oxygen containing gas and a complex metal-amine catalyst, preferably a copper (I)-amine catalyst, as the oxidizing agent and, preferably extracting at least a portion of the metal catalyst as a metal-organic acid salt with an aqueous containing solution, and functionalizing the PPE with the addition of at least one unsaturated anhydride of the formula (I) prior to and/or during at least one isolation step for removal of the reaction solvent. In one embodiment, the functionalization is at least partly done in a flash process to concentrate the PPE reaction solution. In another embodiment, the functionalization is at least partly done prior to a flash process to concentrate the PPE reaction solution. In yet another embodiment, the functionalization is at least partly done in a devolatilizing extruder. The functionalization reaction is preferably done in the presence of at least one catalyst, preferably an amine-type catalyst. These and other embodiments will become apparent in the description that follows.
The PPE employed in the present invention are known polymers comprising a plurality of structural units of the formula (VI):
wherein each structural unit may be the same or different, and in each structural unit, each Q1 is independently halogen, primary or secondary lower alkyl (i.e., alkyl containing up to 7 carbon atoms), phenyl, haloalkyl, aminoalkyl, hydrocarbonoxy, or halohydrocarbonoxy wherein at least two carbon atoms separate the halogen and oxygen atoms; and each Q2 is independently hydrogen, halogen, primary or secondary lower alkyl, phenyl, haloalkyl, hydrocarbonoxy or halohydrocarbonoxy as defined for Q1. Most often, each Q1 is alkyl or phenyl, especially C1-4 alkyl, and each Q2 is hydrogen.
Both homopolymer and copolymer PPE are included. The preferred homopolymers are those containing 2,6-dimethyl-1,4-phenylene ether units. Suitable copolymers include random copolymers containing such units in combination with (for example) 2,3,6-trimethyl-1,4-phenylene ether units. Also included are PPE containing moieties prepared by grafting vinyl monomers or polymers such as polystyrenes and elastomers, as well as coupled PPE in which coupling agents such as low molecular weight polycarbonates, quinones, heterocycles and formals undergo reaction in known manner with the hydroxy groups of two poly(phenylene ether) chains to produce a higher molecular weight polymer, provided a substantial proportion of free OH groups remains.
The molecular weight and intrinsic viscosity of the PPE can vary widely, depending at least in part on the intended end-use for the PPE. The intrinsic viscosity (hereinafter xe2x80x9cI.V.xe2x80x9d) of the PPE is most often in the range of about 0.08-0.60 dl./g., preferably in the range of about 0.10-0.49 dl./g., more preferably in the range of about 0.10-0.30 dl./g., as measured in chloroform at 25xc2x0 C. In one especially preferred embodiment, the PPE has an I.V. in the range of about 0.10-0.25 dl./g. One unexpected aspect of the process is the ability to utilize a very wide range of I.V.
The PPE are typically prepared by the oxidative coupling of at least one monohydroxyaromatic compound such as 2,6-xylenol, 2,3,6-trimethylphenol, or mixtures of the foregoing by methods known in the art. Catalyst systems are generally employed for such coupling and they typically contain at least one heavy metal compound such as a copper, manganese, or cobalt compound, usually in combination with various other materials.
It will be apparent to those skilled in the art from the foregoing that the PPE contemplated in the present invention include all those presently known, irrespective of variations in structural units or ancillary chemical features.
The functionalizing agents used in the present invention to introduce the aliphatic unsaturation onto the PPE are unsaturated compounds of the formula (I):
wherein R1 is an aliphatic or aromatic residue, for example, xe2x80x94CH2xe2x80x94 but may be multiple xe2x80x94CH2xe2x80x94 groups, e.g., n can vary from 1 to about 10 or more, or alternatively, n may equal zero wherein the formula is an acrylic residue, and wherein each of R2, R3, and R4 are independently hydrogen, alkyl, or aryl, and wherein X is a residue of one of the following formulae (II):
alternatively, X may be a halogen or may be a residue of the formula (III):
wherein R7 is an aliphatic or aromatic residue, for example, xe2x80x94CH2xe2x80x94 but may be multiple xe2x80x94CH2xe2x80x94 groups, e.g., m can vary from 1 to about 10 or more, or alternatively, m may equal zero (wherein if n and m both equal zero, the unsaturated compound is an acrylic anhydride), and wherein each R8, R9, and R10 are independently hydrogen, alkyl, or aryl. In a preferred embodiment, the unsaturated compound is of the formula (IV):
wherein each of n, R1, R2, R3, and R4 are as previously described. In an especially preferred embodiment, the unsaturated compound is of the formula (V):
However, included within the scope of the present invention are xe2x80x9cmixedxe2x80x9d or xe2x80x9cunsymmetricalxe2x80x9d anhydrides of formula (IV).
Although not wishing to be bound by any theory on the nature or mechanism of the chemical reaction between the PPE and the unsaturated compound of formula (I), it is presumed that the functionalization of the PPE takes place through the hydroxyl groups on the PPE resulting in a PPE containing aliphatic unsaturation comprising the formula (VII):
each of Q1, Q2, n, R1, R2, R3, and R4 is as previously defined and j comprises a range of values generally on average between about 10 and 110 depending in large part on the I.V. of the PPE. In one embodiment, j has an average value less than 49. In another embodiment, j has an average value less than 34. In a preferred embodiment, the PPE containing aliphatic unsaturation comprises the formula (VIII):
each of n, j, R1, R2, R3, and R4 is as previously defined. In an especially preferred embodiment, n is zero, R2 is CH3 or hydrogen and both of R3 and R4 are hydrogen. There can also be multiple aliphatic unsaturation introduced onto the PPE through incorporation of branching agents and/or coupling agents into the PPE backbone structure such that more than one end of the PPE contains hydroxyl groups for capping. Such branching agents and/or coupling agents are known in the art and include compounds such as, for example, tetramethylhydroquinone and trishydroxyphenol.
The functionalization reaction is preferably performed in a solvent, preferably in the polymerization reaction solvent. Suitable solvents are disclosed in the above-noted Hay patents. Aromatic solvents such as benzene, toluene, ethylbenzene, xylene, and o-dichlorobenzene are especially preferred, although tetrachloromethane, trichloromethane, dichloromethane, 1,2-dichloroethane and trichloroethylene may also be used.
One unexpected advantage of the present process when used to make functionalized low I.V. PPE is that a higher solids loading is possible as compared to processes that make higher (i.e.  greater than 0.28 I.V.) PPE. Without the increased solution viscosity build that concomitantly accompanies high molecular weight polymer, the final solids concentration can be increased by at least 20%, with increases of 30% or more possible. Thus, the present process affords a method for increased reactor utilization and productivity without increasing the size or number of the reactor vessels.
The temperature to carry out the functionalization stage of the invention generally ranges from about 20xc2x0 C. to about 100xc2x0 C., although higher temperatures are also possible. More preferably, the temperature range is from about 45xc2x0 C. to about 80xc2x0 C. At substantially higher temperatures, side reactions can occur leading to reaction by-products. One unexpected advantage of the present process is the relatively low temperatures that can be utilized and still achieve high levels of functionalization at acceptable reaction times.
After removal of the catalyst, the PPE containing solution is concentrated to a higher solids level as part of the isolation of the PPE. It was unexpectedly found that PPE can be readily functionalized to a PPE containing aliphatic unsaturation prior to and/or during this solvent removal process by addition of at least one functionalizing agent of the formula (I). The location of the addition of the at least one functionalizing agent will depend on several factors such as the stability of the agent, the volatility of the agent to the isolation conditions, the flexibility of the equipment for addition points, and the like. For functionalizing agents that are volatile in the isolation process, addition of the functionalizing agent prior to solvent removal is often preferred so as not to remove the functionalizing agent before it has functionalized the PPE. For less volatile functionalizing agents, greater flexibility in the location of the addition is possible. It is also possible to add functionalizing agent at several points during the process.
The amount of the above mentioned functionalizing agents that is required to appropriately functionalize the PPE is that which is sufficient to improve the compatibility between the various components in the final composition, i.e. between the PPE and the other resins and composite formulations, e.g., unsaturated polyesters, acrylics, and thermoplastics such as polyolefins. As previously discussed, indications of improved compatibility include resistance to delamination, improved physical properties such as increased tensile and impact properties and a stabilized morphology between the blend component phases under static or low shear conditions. For the most part, it is desirable for all hydroxy end groups on the PPE to be capped by the method of this invention. However, the invention includes compositions which contain a proportion of uncapped PPE; that is, PPE containing terminal hydroxy groups.
An effective amount of the above mentioned unsaturated compounds, based on the amount of the PPE, is generally up to about 3 molar equivalents, and is preferably up to about 2 molar equivalents, most preferably up to about 1.2 molar equivalents, all based upon the amount of terminal hydroxyl groups on the PPE as determined by FT-IR, usually in carbon disulfide. The actual amount utilized will also depend on, for example, the reactivity of the unsaturated functionalizing agent with the PPE hydroxyl groups, the catalyst employed, the reaction conditions, and the degree of capping that is desired in the PPE.
The capping efficiency and rate are improved by the addition of at least one catalyst. Although a wide variety of catalysts are useful, a particularly useful group of catalysts include the tertiary amines. It was unexpectedly found that 4-dialkylaminopyridines, such as 4-dimethylaminopyridine, as well as 4-pyrrolidinopyridine are especially useful for achieving high conversions at short reaction times under mild conditions as compared to other tertiary amines. The amount of catalyst can vary widely, however, the amount is generally an amount effective to improve the degree of conversion under a given set of reaction conditions as compared to the degree of conversion under the same conditions without the catalyst. Useful amounts generally range from about 0.1% by weight to about 10% by weight, preferably from about 0.5% by weight to about 5% by weight based on the amount of the PPE. An exact amount can be readily determined by statistical analysis under the reaction conditions, including the actual functionalizing agent reactivity, the reaction conditions, the equipment available, and the like without undue experimentation.
The functionalized PPE may be isolated in a variety of ways, including precipitation methods and total isolation methods. A total isolation process is often preferred for isolating the functionalized PPE when the I.V. is less than about 0.25 dl/g as measured in chloroform at 25xc2x0 C. As part of the total isolation, a portion of the solvent is preferably removed in order to reduce the solvent load on the total isolation equipment. Concentration of the PPE containing solution is preferably accomplished by reducing the pressure in a solvent flash vessel while preferably increasing the temperature of the PPE containing solution. Pressures of about 35 to 50 bar are desirable with solution temperatures increased to at least 200xc2x0 C., preferably of at least 230xc2x0 C. A solids level of PPE of at least 55%, preferably of at least 65% or higher is desirable.
The unsaturated functionalizing agent can be effectively added to the PPE at several locations during the isolation process. For example, functionalizing agent may be added prior to removal of solvent, the functionalizing agent may be added during the concentration of the reaction mixture, or both. Likewise, functionalizing agent can be added with the concentrated reaction solution into the final devise for solvent removal. Functionalizing agent may alternatively be added simultaneously at several different locations. The selection of the addition location may be dictated by the actual equipment utilized and by the properties of functionalizing agent with a determination of an optimum location.
For total isolation processes, the final isolation of the functionalized PPE is preferably carried out in a devolatilizing extruder although other methods involving spray drying, wiped film evaporators, flake evaporators, and flash vessels with melt pumps, including various combinations involving these methods are also useful and in some instances preferred. As previously described, total isolation is preferable from the viewpoint that oligomeric species are not removed to the same degree as with precipitation. Likewise, isolation yields are extremely high and are near quantitative. In these techniques it is highly preferred that the PPE polymerization catalyst (i.e. metal catalyst) removal be completed in the prior process steps as any metal catalyst remaining in solution will necessarily be isolated in the PPE.
Devolatilizing extruders and processes are known in the art and typically involve a twin-screw extruder equipped with multiple venting sections for solvent removal. The devolatilizing extruders most often contain screws with numerous types of elements adapted for such operations as simple feeding, devolatilization and liquid seal formation. These elements include forward-flighted screw elements designed for simple transport, and reverse-flighted screw and cylindrical elements to provide intensive mixing and/or create a seal. Particularly useful are counterrotating, non-intermeshing twin screw extruders, in which one screw is usually longer than the other to facilitate efficient flow through the die of the material being extruded. Such equipment is available from various manufacturers including Welding Engineers, Inc.
In the practice of one embodiment of the present invention, the preheated concentrated solution containing the functionalized PPE is fed into the devolatilizing extruder and maintained at a temperature less than about 300xc2x0 C., and preferably less than about 275xc2x0 C., with pressures in the vacuum vent of less than about 1 bar. The exact temperature will depend in large part on the I.V. of the functionalized PPE and the corresponding viscosity associated with that I.V. resin. It is noted that the functionalizing agent may alternatively be added at various locations along the length of the extruder with good results. The resultant solvent level is preferably reduced to less than about 1200 ppm, preferably less than about 600 ppm, and most preferably less than about 400 ppm.
Another unexpected result obtained through the use of a devolatilizing extruder was the extremely high yield of PPE achieved in the process. For example, a PPE yield of over 99% was obtained even for PPE having a low I.V. (typically on the order of about 0.08 dl/g to about 0.25 dl/g) whereas in the precipitation process known in the art, the yield of similar low I.V. PPE was less than 90%. Thus, the present process comprising a devolatilizing extruder affords a method to prepare functionalized low molecular weight polyphenylene ether resin containing aliphatic unsaturation, typically within the intrinsic viscosity range of about 0.08 dl/g to about 0.25 dl/g, in a yield of over 90%, preferably over 95%, more preferably over 98% and most preferably over 99%, based upon the amount of monovalent phenol utilized in the oxidative coupling.
When using a devolatilization extruder for the total isolation of the low I.V. functionalized PPE as previous described, it was found that traditional underwater or water spray cooling of strands of extrudate followed by chopping the extrudate into pellets gave unacceptable results presumably due to the low melt strength and inherent brittle nature of low I.V. PPE. It was found that special pelletization techniques can overcome these difficulties. Useful techniques include die-face pelletization, including underwater pelletization and flaking, declining angle strand pelletization using water spraying, and vibration drop pelletization with underwater pelletization especially suitable.
The collected PPE pellets can be dried using techniques standard in the art including centrifugal dryers, batch or continuous oven dryers, fluid beds, and the like. Determination of an appropriate set of conditions can be readily determined by one of skill in the art without undue experimentation.
As an alternative to completely isolating the functionalized PPE, one or more resins may be added to the devolatilized functionalized PPE in the same process. The one or more resins may be fed into the devolatilizing extruder although additional extruders may also be used. Possible variations include melt feeding the one or more resins into the devolatilizing extruder or melt feeding the functionalized PPE from the devolatilizing extruder into a second compounding extruder as well as combinations of these. Accordingly, in one embodiment a compatibilized blend is afforded by the process without complete isolation of the functionalized PPE. The one or more resins can vary widely and can also include additives common to such compatibilized blends. Such additives include impact modifiers, lubricants, flame retardants, pigments, colorants, fillers, reinforcing agents, carbon fibers and fibrils, and the like. Preferred resins include polyamides, polyesters, polyarylene sulfides, polycarbonates, polyetherimides, polyarylenes, functionalized polyolefins, polysulfones, polyethersulfones, and the like.
The functionalized PPE containing aliphatic unsaturation is especially useful in composite systems that involve a curing or polymerization step of unsaturated species, for example, styrene or acrylic-type monomers. It is believed that the aliphatic unsaturation introduced onto the PPE affords a reaction path to chemically link the PPE into composite system. Moreover, many of these same composite systems cure or polymerize, at least in part, through radical reactions. Uncapped PPE contains phenyl hydroxyl moieties that interfere with such radical reactions. In one embodiment, the functionalized PPE containing aliphatic unsaturation has the free hydroxyl groups xe2x80x9ccappedxe2x80x9d reducing the interference. By xe2x80x9ccappedxe2x80x9d is meant that at least about 80%, preferably at least about 90%, more preferably at least about 95% or more of the hydroxyl groups of the PPE have been reacted. It should be clear that the present invention also includes reaction products between the PPE containing aliphatic unsaturation and composite systems that involve a curing and/or polymerization step of unsaturated species. It should also be clear that the PPE containing aliphatic unsaturation is useful with a wide range of thermosetting resins, including but not limited to those selected from the group consisting of epoxy, phenolic, alkyds, polyester, polyimide, polyurethane, mineral filled silicone, bis-maleimides, cyanate esters, vinyl, and benzocyclobutene resins and can react in a variety of pathways with such resins.
All patents cited by reference are incorporated herein by reference.
In order that those skilled in the art will be better able to practice the invention, the following examples are given by way of illustration and not by way of limitation.

Compositions comprising functionalized polyphenylene ether resins


This invention relates to the compositions and method of treating and preventing arthritis, repairing of articular joint surfaces and the relief of symptoms associated with arthritis. The composition comprises bio-affecting agents to reduce nitric oxide production and increase chondroprotective agents. The preferred composition comprises; nitric oxide synthase inhibitors, nitric oxide scavangers, and amino sugars. Nitric oxide synthase inhibitors and nitric oxide scavengers reduce the level of nitric oxide, the free radical responsible for the degradation of articular cartilage. Amino sugars are the building blocks of articular cartilage and have anti-inflammatory actions.

The present invention concerns compositions and methods of treating and preventing arthritis, repairing of articular joint surfaces and relief of symptoms associated with arthritis.
Arthritis, a musculoskeletal disorder, is the leading cause of disability in the United States. The Centers for Disease Control and Prevention (CDC) stated that arthritis and other rheumatic conditions accounted for about 744,000 hospitalizations and 4 million days of care in 1997. Forty million Americans, representing 15% of the population, have some form of arthritis, and that figure is expected to increase to 59.4 million (18.2%) by the year 2020, an increase of 57% in the number of persons affected. Arthritis patients make more than 315 million physician visits and are hospitalized more than 8 million times a year. Arthritis costs the nation $65 billion annually in medical costs and lost productivity. Osteoarthritis (OA), or degenerative joint disease, is the most common type of arthritis, affecting 20.7 million people, (12.1%) of U.S. adults in 1990, now estimated at 37 million, and trailed chronic heart disease as the leading cause of Social Security payments due to long-term absence from work. Lawrence R C, et al. Arthritis and Rheumatism 1998;41 :778-799.
Approximately 1-2% of the population suffers from rheumatoid arthritis (RA), which is characterized as an imbalance in the immune system that causes an overproduction of pro-inflammatory cytokines, e.g., tumor necrosis factor alpha (TNFxcex1), interleukin 1 (IL-1), and a lack of anti-inflammatory cytokines, e.g. IL-10, IL-11. RA is characterized by synovial inflammation, which progresses to cartilage destruction, bone erosion and subsequent joint deformity. The primary symptoms of RA are joint inflammation, swelling, difficulty moving, and pain. During the inflammatory process, polymorphonuclear cells, macrophages, and lymphocytes are released. Activated T-lymphocytes produce cytotoxins and pro-inflammatory cytokines, while macrophages stimulate the release of prostaglandins and cytotoxins. Vasoactive substances (histamine, kinins, and prostaglandins) are released at the site of inflammation and cause edema, warmth, erythema, and pain associated with inflamed joints.
Osteoarthritis usually presents as pain, which worsens with exercise or simply an X-ray that clearly shows thinning cartilage. Common joints affected are the knees, hips and spine, finger, base of thumb and base of the big toe. Osteoarthritis is characterized by degenerative changes in the articular cartilage and subsequent new bone formation at the articular margins. The primary defect in hyaline cartilage, at the articular surface of the joint, is an alteration in the ratio of total glycosaminoglyeans to that of the collagen fiber content in the matrix. Yasuda K. Hokkaido Igaku Zasshi July 1997;72(4):369-76. Paleontologists have found osteoarthritis to exist in almost every vertebrate. By age 60, almost all Americans have osteoarthritis in their necks or spines. Joint cartilage consists of only 5 percent cells, and that joint cartilage lesions do heal. Tindall W N. Business and Health December 1997;47-48. Bones directly underneath the cartilage in joints is called subchondral bone. This bone nourishes the cartilage with oxygen, water, and nutrients conveyed through microscopic channels. This supply route carries xe2x80x9cchondroprotective agentsxe2x80x9d from the bloodstream to the cartilage.
Cartilage is the supporting structure of the body, but has no blood vessels, nerves or lymphatics, and consists of thick bundles of fibrous protein (collagen) which are woven to form the articular surface. Proteoglycans fill the extracellular spaces not occupied by collagen, and are a combination of protein and sugar. Each proteoglycan subunit contains a protein core attached to hundreds of long chains of specially modified sugars called glycosaminoglycans (GAGs). Glucosamine is the single most important component and precursor for GAGs. Glucosamine is almost completely absorbed by the GI tract into the bloodstream. Cartilage rebuilding is only as good as its GAG synthesis. Chondrocytes in the cartilage obtain glucosamine from the subchondral blood vessels and manufacture N-acetylglucosamine (NAG) and glucuronic acid, which make hyaluronan, which is half glucosamine, and provides the lubricating ability of joints.
There is no definitive answer regarding the cause of osteoarthritis. A natural erosion of cartilage occurs with age, but excessive loads placed on joints, obesity, heredity, trauma, decreased circulation, poor bone alignment, and repetitive stress motion play a role. Osteoarthritis may also be the result of free radical damage, thought to be a major cause of many diseases, including the aging process, cancer, heart disease and degenerative diseases.
Free radicals affect the immune system causing rheumatoid arthritis and osteoarthritis. Free radicals are atoms or atomic groups that are byproducts of normal metabolism, tobacco smoke, pollutants, car exhaust, bacteria, radiation, and chemicals which oxidize or damage otherwise healthy cells. They damage DNA, corrode cell membranes, and may play a role in the development of cancer, heart and lung disease, cataracts, and cause or accelerate the aging process. Bucci wrote that there is conclusive evidence that free radicals do most of their damage in rheumatoid arthritis, but also to the cartilage in osteoarthritis. Bucci L. Healing Arthritis the Natural Way Arlington, Tex.: Summit Publishing Group, 1995, pp. 34-5. In his best seller, Theodosakis stated that xe2x80x9cOsteoarthritis may be the result of free radical damage. And to make matters worse, joint inflammation itself may trigger an even faster rate of new free radical formation. Prevention of free radical damage is a critical feature in treating and preventing osteoarthritis.xe2x80x9d Theodosakis J, Adderly B, Fox B. The Arthritis Cure New York, St. Martins Press, 1997, p 147-9. Unless the damage caused by free radical formation is addressed, any benefits obtained by using only chondroprotective agents could be nullified; similar to trying to fill a sieve with water, the relief is transient but pathology progresses.
There is no known drug that claims to reverse osteoarthritis. Most therapeutic agents are directed at reducing the inflammation and relieving pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first line of treatment for osteoarthritis, but long-term use can lead to gastric ulcers, kidney damage, hearing loss and even inhibit cartilage formation.
This invention relates to the compositions and method of treating and preventing arthritis, repairing of articular joint surfaces and the relief of symptoms associated with arthritis. Inhibitors of nitric oxide production comprise nitric oxide synthase inhibitors and nitric oxide scavengers that reduce the level of nitric oxide, the free radical responsible for the degradation of articular cartilage. Amino sugars are the building blocks of articular cartilage and have anti-inflammatory actions.
Osteoarthritis is thought to be the result of decreased production and increased degradation of the cartilaginous matrix. Loss of this protective layer leads to roughening and fissuring of the cartilage and may eventually cause erosion severe enough to expose the bone. The current goal of osteoarthritis therapy is the relief of pain. NSAID use is limited by the fact that they do not change the natural course of the disease and may accelerate joint deterioration in the long run.
The present invention relates to novel compositions of bio-affecting agents for the prevention and treatment of arthritis. The term bio-affecting agent refers to any chemical substance or formulation which beneficially affects the body. The bio-affecting agents of the preferred composition comprises; nitric oxide synthase inhibitors, nitric oxide scavangers, amino sugars, zinc compounds, methyl-sulfonyl-methane, enzymes, glycosaminoglycans, vitamin A, vitamin B, vitamin C, vitamin E, analgesics, anti-inflammatory agents, enzymes, alpha-lipoic acid, aloe vera extract, antioxidants, anthocyanidins, proanthcyanidins, and herbal derivatives.
The maintenance of articular cartilage requires a balance between anabolic and catabolic processes. An increase in some cytokines, such as interleukin-1 (IL-1), is associated with a decrease in the synthesis and increase in the degradation of proteoglycans and collagens necessary for the structural integrity of the cartilaginous matrix. While cytokines, such as transforming growth factor (TGF.), stimulates chondrocyte synthesis of collagens and proteoglycans, reduces the activity of IL-1-stimulated proteinases, and opposes the inhibitory and catabolic effects of IL-1. Patients presenting with either rheumatoid arthritis (RA) or osteoarthritis (OA) have been observed to have increased levels of NO in the synovial fluid. A significant source of NO production in these patients appeared to be articular chondrocytes. Henrotin Y E, et al, Nitric oxide downregulates cytokines, J of Rheumatology 1998;25(8):1595-1601. Nitric oxide (NO) is produced by articular chondrocytes in large amounts for extended periods of time by an inducible form of nitric oxide synthase (NOS) in response to activation by IL-1 and other agents. An increase in NO decreases the synthesis of proteoglycans and type II collagen. If NO production is blocked with the use of NG-monomethyl-L-arginine (L-NMA), an inhibitor of NOS, inhibition of proteoglycan synthesis by IL-1 is blocked, and concentration of TGF is increased. Studer R K, Georgescu H I, Miller L A, Evans C H, Inhibition of transforming growth factor production by nitric oxide-treated chondrocytes, Arthritis and Rheumatism 1999;42(2):248-257.
Nitric oxide is a short lived, gaseous free radical that is synthesized from the terminal guanidino nitrogen of L-arginine in an oxidation reaction catalyzed by NOS. NOS expression is inducible by endotoxin, cytokines, growth factor and immune complexes. The overexpression of NOS in rheumatoid arthritis (RA) may result from increased levels of tumor necrosis factorxe2x80x94(TNF), IL-1, and other proinflammatory cytokines characteristic of this disease. Chondrocytes from patients with OA and RA spontaneously over express NOS and produce elevated levels of NO. St. Clair E W, Nitric oxidexe2x80x94friend or foe in arthritis? J of Rheumatology 1998;25(8):1451-1453.
Canadian researchers reduced the progression of experimental osteoarthritis in dogs by inhibiting inducible nitric oxide synthase (NOS). Pelletier J P, et al. Arthritis and Rheumatism 1998;41:1275-1286. Pelletier reported that osteoarthritis cartilage produced an increased amount of nitric oxide (NO) due to an increased level of inducible nitric oxide synthase in cartilage chondrocytes. Nitric oxide plays an important role in autoimmunity and inflammation. Normal cartilage does not produce NO or express NOS unless stimulated with cytokines. In the joint, NO, produced in response to cytokine stimulation, exerts a number of catabolic effects on chondrocyte functions which would be expected to promote the degradation of articular cartilage. These effects of NO on chondrocytes include: inhibition of collagen and proteoglycan synthesis, activation of metalloproteinases, increased susceptibility to injury by other oxidants, inhibition of actin polymerization, and apoptosis. NSAIDs, such as aspirin, and to a lesser extent, sodium salicylate, and tetracycline inhibit the expression of NOS protein. Clancy R M, Amin A R, Abramson S B. Arthritis and Rheumatism 1998;41 :1141-1151. Nitric oxide was shown to inhibit the respiration and ATP synthesis of chondrocytes and suppressed the synthesis of proteoglycans. Tomita M, et al, Arthritis and Rheumatism 2001;44:96-104.
The present invention of nitric oxide synthase inhibitors and nitric oxide scavangers include, but are not limited to: nitric oxide synthase inhibitors; which includes arginine-based analogues such as methylated arginines, substituted L-arginine, nitro-arginine, L-NG-nitroarginine, NG-mono-methyl-L-arginine (L-NMMA), N-nitro-L-arginine methyl ester (L-NAME), N-amino-L-arginine, N-methyl-L-arginine, NG-monomethyl-L-arginine (L-NMA), NG-nitro-L-arginine (L-NNA), aminoguanidine, 7-nitroindazole, S-ethylisothiourea, S-methylisothiourea, S-methylthiocitriulline, S-ethylthiocitrulline, N-ethylimino-L-omithine, N-iminoethyl-L-lysine (L-NIL), flavoprotein binders such as diphenylene iodonium and related iodonium derivatives, omithine and ornithine derivatives; tetracycline; L-canavanine; citrulline; redox dyes such as methylene blue; calmodulin binders such as trifluoropiperazine and calcinarin; heme binders; resveratrol; vitamin B derivatives, such as niacinamide; zinc compounds; tetrahydropterin analogs such as aminoguanidine; and depleters of biopterin such as methotrexate, and N-acetylcysteine.
Resveratrol (3,5,4xe2x80x2-trihydroxystilbene), an antioxidant found in wine, can inhibit the action of cyclo-oxygenase and lipo-oxygenase enzymes and inhibit the release of pro-inflammatory eicosanoids, leukotrienes and platelet aggregation promoters. Sato M, el al Biosci Biotechnol Biochem November 1997;61(11):1800-5. Resveratrol also suppresses nitric oxide synthase. Tsai S H, et al, Br. J Pharmacol February 1999;126(3):673-80. Resveratrol was shown to inhibit tumor necrosis factor-alpha (TNF-alpha) and nitric oxide production. Kawada N Hepatology May 1998;27(5):1265-74. Resveratrol dosage range is 5 to 10 mg per day or 250 mg as a lyophilized grape extract. Topical dosage range is 2 to 3 mg.
Niacinamide is one of the water-soluble B-complex vitamins. Niacinamide has multiple functions such as inhibition of poly-ADP-ribose synthetase, inhibition of inductible nitric oxide synthase, free radical scavenging, suppression of major histocompatibility complex class II expression and ICAM-1 expression on endothelial cells and inhibitory effect on the production of TNF-alpha. Fukuzawa M, et al, Immunol Lett October 1997;59(1):7-11.
The use of NOS inhibitors is well known in the art. Dawson et al, U.S. Pat. No. 5,266,594, discloses a method of preventing or treating glutamate neurotoxicity with a NOS inhibitor capable of penetrating the blood brain barrier. Ahluwalia et al, U.S. Pat. No. 5,468,476, discloses a method of reducing hair growth with a NOS inhibitor. Wahl et al, U.S. Pat. No. 5,449,688, discloses a method for treating chronic inflammatory conditions by parenterally or intravenously administering a NOS inhibitor. Stamler et al, U.S. Pat. No. 5,545,614, discloses a method for stimulating skeletal muscle contractions with a NOS inhibitor. Moncada et al, U.S. Pat. No. 5,585,402, discloses a method for inhibiting tissue damage by using a NOS inhibitor to decrease NO production in vascular endothelial cells. Dunn et al, U.S. Pat. No. 5,665,757, discloses a method for treating anxiety using a NOS inhibitor. Mjalli et al, U.S. Pat. No. 5,723,451, discloses a method for inhibiting NOS using one of eleven formulations. None of the above cited patents teach or suggest the use of the composition and method outlined in the present invention.
Agents that may repair, or at the very least, slow the degradation of articular cartilage have been described as possessing chondroprotective properties. Examples of these agents include: heparinoids (Arteparon, Rumalon), hyaluronic acid, piroxicam, tetracyclines, corticosteroids, chondroitin, and glucosamine sulfate. Da Camara C C, Dowless G V. Annals of Pharmacotherapy 1998;32:580-7.
Glucosamine from exogenous sources (food and supplements) may stop the progression of cartilage degradation and stimulate the production of new cartilage. Glucosamine absorbed by the gastrointestinal tract undergoes significant first-pass metabolism in the liver, with the resulting 26% bioavailibility. It is incorporated into plasma proteins as a result of hepatic metabolism, and concentrates in the articular cartilage. Clinical improvement of symptoms has been seen as early as one week after oral administration of glucosamine sulfate and has persisted for up to four weeks after discontinuation. Barclay T S, Tsourounis C, McCart G M. Glucosamine. Annals of Pharmacotherapy 1998;32:574-79. A three-year study of 212 patients with knee osteoarthritis showed long-term combined with structure-modifying and symptom-modifying effects of glucosamine sulfate. Reginster J Y, et al, Lancet 2001;357:251-56. Oral glucosamine was demonstrated to be utilized in newly synthesized proteoglycan and end up in the cartilage matrix. Noyszewski E A, et al, Arthritis and Rheumatism 2001;44:1089-1095.
Several commercial forms of glucosamine are available, including the sulfate, hydrochloride, N-acetylglucosamine (NAG). Glucosamine hydrochloride has a higher concentration of glucosamine than the sulfate form. NAG is rapidly metabolized to make proteins and provides less glucosamine for cartilage repair. The composition of the invention could include one or a combination of the glucosamine forms. Patients have reported a more rapid response with higher dosages of glucosamine, but the therapeutic results with glucosamine alone have not been consistent. The dosage range for glucosamine can vary from 500 mg to 3000 mg a day, in divided doses, depending on body weight and severity of symptoms. One approach is to take 1,500 mg of glucosamine daily until symptoms have decreased, then reduce the dosage to 1,000 mg for two weeks and eventually stop treatment after symptoms cease or stay on a maintenance dose of 500 mg per day.
Adverse effects reported from glucosamine are gastrointestinal, such as heartburn and epigastric pain. Because the half-life of glucosamine in the blood is relatively short, a sustained-release form of the compound could avoid the adverse effects and provide a more uniform blood level. Talent J M, Gracy R W. Clinical Therapy 1996;18(6):1184-90.
The use of amino sugars is well known in the art. Jacobi, U.S. Pat. No. 3,859,436, discloses a topical composition of glucose, fructose, glucosamine and desoxyribose and ribose. Prudden, U.S. Pat. No. 4,006,224, discloses a method for treating inflammatory disorders of the gastrointestinal tract with D-glucosamine. Meisner, U.S. Pat. No. 4,590,067, discloses a composition for the prevention and treatment of periodontal disease comprising, bone meal, tyrosine, glucosamine and ascorbic acid. Speck, U.S. Pat. No. 4,870,061, discloses a method for treating degenerative joint disease by buccal administration of N-acetylglucosamine. Kludas, U.S. Pat. No. 5,036,056, discloses a method for treating damaged connective tissue with a connective tissue matrix of collagens, proteoglycans, glycosaminoglycans and glycoproteins. Henderson, U. S. Pat. Nos. 5,364,845 and 5,587,363, discloses a composition for the repair of connective tissue comprising glucosamine, chondroitin sulfate and manganese. Williams et al, U.S. Pat. No. 5,679,344, discloses a composition for articular disorders comprising glucosamine and proteases. Diaz et al, U.S. Pat. Nos. 5,795,576 and 5,891,441, discloses a composition and method for the elimination of undigested fat prior to digestion comprising, psyllium, glucosamine, glucomannan, apple pectin and stearic acid. Murad, U.S. Pat. No. 5,804,594, discloses an oral composition for improving skin conditions comprising, N-acetylglucosamine, ascorbic acid, amino acids, and a transition methal composition. Florio, U.S. Pat. No. 5,840,715, discloses a composition of nutritional supplements of gamma linolenic acid, eicosapentaenoic acid and docosahexaneoic acid, chondroitin sulfate, N-acetylglucosamine sulfate, glucosamine sulfate and manganese aspartate. Platt, U.S. Pat. No. 5,891,861, discloses a composition of oligomers of beta glucosamine to treat fungal diseases. Weisman, U.S. Pat. No. 5,888,514, discloses a composition of natural ingredients for treating bone and joint inflammation using shark cartilage, glucosamine, herbs and enzymes. None of the above cited patents teach or suggest the composition or method outlined in the present invention.
Chondroitin sulfate is the major GAG in cartilage, and has a synergistic effect with glucosamine, but poorly absorbed by oral administration. Chondroitin sulfate is half galactosamine, which is made directly from glucosamine, and has great water retaining ability. Dosage range of chondroitin sulfate is 250 mg to 1,000 mg per day in divided doses. Morrison, U.S. Pat. No. 3,895,107, discloses a method of inhibiting atherosclerotic lesions by administering chondroitin sulfate. Walton et al, U.S. Pat. No. 4,489,065, discloses the binding of drugs to chondroitin for the controlled release of the drug. None of the above cited patents teach or suggest the use of the composition and method outlined in the present invention.
Zinc plays a physiological role in the regulation of bone metabolism, by stimulating bone formation and mineralization and an inhibitory effect on bone resorption. Zinc activates aminoacyl-tRNA synthetase in osteoblastic cells, stimulates cellular protein synthesis, and inhibits osteoclast-like cell formation in marrow cells. Bone zinc content is decreased by development, with aging, skeletal unloading, and postmenopausal conditions. Zinc plays a role in the preservation of bone mass. Most zinc compounds, such as zinc sulfate, are useful for the prevention of osteoporosis, but a recent study confirmed thatxe2x80x94Alanyl-L-histidinato zinc (AHZ) has a potent effect on bone formation and calcification. Yamaguchi M, Role of Zinc in Bone Formation and Bone Resorption, J of Trace Elements and Experimental Medicine 1998; 11:119-135. The thickening of subchondral bone in osteoarthritis may be a prelude to cartilage breakdown. The phosphate-to-protein and carbonate-to-protein ratios rise with increasing severity of symptoms in osteoarthritis. Lewis R A, Biophotonics International 2001;January-February:67.
Zinc compounds have anti-inflammatory and anti-infective properties. In Current Therapeutic Research, 1998; 59/9: 595-607, the inventor served as chief investigator for a randomized, double-masked, placebo-controlled clinical study of the effectiveness of zinc acetate lozenges on common cold symptoms in allergy-tested subjects. Those subjects who used the zinc lozenges had both a shorter duration and severity of common cold symptoms. Those subjects who were positive for allergies, were more responsive to zinc by having a shorter duration of nasal symptoms. The study cited many references that reported the benefits and effects of zinc compounds.
Zinc is an essential mineral found in every form of life on earth. Unlike other metals, zinc is virtually nontoxic. Zinc and its compounds have long been recognized as possessing certain therapeutic functions. Zinc compounds are acknowledged as astringents and beneficial in wound healing, reducing inflammation, and has antimicrobial, antifungal and antiviral activity. Zinc is the active agent in formulations to treat diaper rash, decubitus ulcers, and abrasions. Zinc stabilizes the cell membranes and inhibits the formation of free radicals. Zinc also strengthens the integrity of blood vessel walls by reducing the membrane permeability and stopping bleeding.
Zinc has an inhibitory effect on the release of histamine from mast cells due to its stabilizing effect of the mast cell membrane. Most mast cells contain; Tumor Necrosis Factor a (TNFxcex1) a pro-inflammatory cytokine that causes destruction within the synovium of the arthritic joint and matrix metalloproteinase Type 9 (MMP9) an enzyme that results in collagen degeneration. Kovanen P T, et al, J Am. Coll. Cardiol 1998;32:606-612. The inhibitory effect of zinc on allergy and immunology make it an excellent enhancement to glucosamine and chondroitin therapy. Zinc is also a very potent inhibitor of nitric oxide synthase (NOS). Cuajungco M P, Lees G J Neurobiol Disease 1997;4(34):137-69.
In one form of the invention, the composition uses a zinc salt such as zinc acetate, with the dosage range of 30 to 60 mg per day in divided doses. Zinc salts are selected from a group consisting of, but not limited to: zinc sulfate, zinc chloride, zinc acetate, zinc phenol sulfonate, zinc borate, zinc bromide, zinc nitrate, zinc glycerophosphate, zinc benzoate, zinc carbonate, zinc citrate, zinc hexafluorosilicate, zinc diacetate trihydrate, zinc oxide, zinc peroxide, zinc salicylate, zinc silicate, zinc stannate, zinc tannate, zinc titanate, zinc tetrafluoroborate, zinc gluconate, and zinc glycinate.
Zinc acetate is absorbed throughout the small intestine and has an excellent safety profile. It does not adversely alter serum albumin, bilirubin, aminotransferases, hematologic variables, iron metabolism or renal function indices. Zinc acetate has been assigned to FDA pregnancy category A, indicating that the possibility of fetal abnormalities appears remote. In several trials, no toxic adverse effects have been reported in any patient. The most common adverse effect of zinc therapy is gastrointestinal irritation, which is reported to occur in approximately 10% of patients. Anderson L A, Hakojarvi A L, Boudreaux S K. Annals of Pharmacotherapy 1998;32:78-87. A controlled-release formulation could reduce GI irritation and enhance absorption.
Although any suitable route of administration may be employed for providing the subject with an effective dosage of the composition according to the methods of the present invention, oral administration is preferred. Suitable routes include, for example, oral, rectal, parenteral, intravenous, topical, transdermal, subcutaneous, intramuscular, and like forms of administration may be employed. Suitable dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, suppositories, creams, ointments, gels, and the like, although oral dosage forms are preferred. A topical composition, with a permeation enhancing amount of at least one penetration enhancer, in an appropriate pharmaceutical carrier, could be in the form of a gel, ointment, cream, solution or other means.
The use of pharmaceutical controlled release methods to deliver the composition to the gastrointestinal tract with a desired level of nitric oxide synthase inhibitors, amino sugars and other agents without the adverse gastrointestinal effects is well known in the art.
Enteric coatings are pH sensitive polymers designed to remain intact in the acidic environment of the stomach, but to dissolve in the more alkaline environment of the intestine. Some enteric coatings use blends of cellulose acetate phthalate polymers. Wu et al, U.S. Pat. No. 5,356,634 discloses an enteric coating composition of cellulose acetate phthalate (CAP) and cellulose acetate trimellitate polymers. Crook et al, U.S. Pat. No. 5,723,151 discloses a composition of cellulose acetate phthalate polymer and organic solvent. Some enteric coatings use polyvinylpyrrolidone (PVP). Sipos, U.S. Pat. No. 4,079,125 discloses a binder and stabilizer of PVP and a coating of CAP and diethyl phthalate. Patell, U.S. Pat. No. 4,775,536 discloses the use of an enteric polymer of an acrylic resin and an undercoat and overcoat of PVP. Hodges et al, U.S. Pat No. 5,225,202 discloses an enteric coated composition of hydroxypropylmethyl cellulose phthalate, a plasticizer of triethyl citrate and talc as an anti-adherent.
Some polymers commonly used for enteric coatings are cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP) and acrylic resins. One formulation of the present invention uses 7 mg of polyvinylpirrolidone to coat the immunostimulant composition. The composition can be in the form of a tablet, capsule, granules, or pill for oral administration. Disintegration of the PVP enteric coating occurs in approximately 40 minutes, about the time the composition is in the intestine.
In addition to nitric oxide synthase inhibitors and amino sugars, the following active agents may supplement the composition to promote the development and maintenance of cartilage, include but are not limited to: vitamins, A, B, C, E and their derivatives; minerals, selenium, silica, manganese, magnesium, copper and boron; glycosaminoglycans; analgesics, anti-inflammatory agents, methyl-sulfonyl-methane, S-adenosyl-methionine, alpha-lipoic acid, aloe vera extract, preservatives, antioxidants, stabilizers, surfactants, anti-infective agents, enzymes, collagen type II, adjuvants, anthocyanidins, proanthocyanidins, and herbal derivatives.
Painful arthritis is associated with secondary inflammatory processes in the joint. NSAIDs have proven effective for reducing inflammation, but have gastrointestinal side effects. Proteolytic enzymes (enzymes that have the ability to break down proteins) have been shown to have anti-inflammatory activity, reduce immune complexes, modulate adhesion molecules, activate fibrinolysis, and reduce edema. Plant based enzymes such as bromelain, derived from pineapple stem and papain, derived from papaya, are activated at a temperature higher than normal body temperature and effective at an inflammatory site. Papain, prepared from the stomach of pigs, is also activated at a temperature higher than normal body temperature. Other enzymes effective against inflammation include pancreatin, trypsin, chymotrypsin and rutin. The effective dosage of the enzyme varies with body weight and frequency of administration.
In a further aspect of this invention, for those who have difficulty swallowing a large tablet, due to esophageal strictures or other pathology, a therapeutically effective solution can be administered by a suspension of the active agents in a pharmaceutically acceptable carrier to provide a liquid form to be swallowed or sprayed onto the oral mucosa. By a xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d is meant a composition, solvent, dispersion medium, coating, delivery vehicle or the like, which can be employed to administer the compositions of the present invention without undue adverse physiological effects. A pharmaceutically acceptable carrier can be used to deliver the composition for oral, rectal, parenteral, intravenous, topical, transdermal, subcutaneous and intramuscular administration.
Although illustrative embodiments of the invention have been shown and described, a wide range of modifications, change, and substitution is contemplated in the foregoing disclosure and in some instances, some features of the present invention may be employed without a corresponding use of the other features. Accordingly, it is appropriate that the appended claims be construed broadly and in a manner consistent with the scope of the invention. The above-mentioned patents are hereby incorporated by reference.
This invention is further illustrated by the following examples which are to be regarded as illustrative only, and in no way limit the scope of the invention.

Composition and method of treating arthritis


Pressure is sensed in blood flow tubing by placing an aqueous, preferably isotonic, substantially cell-free solution into branch connection tubing (branch tube) that connects in branching relation with the blood flow tubing at one end. The branch connection tubing may also connect in use with a pressure transducer unit at its other end, or pressure may be mechanically indicated. An air volume is maintained, occupying a portion of the branch connection tubing which is adjacent to the other end. One flows positively or negatively pressurized blood through the blood flow tubing, with the result that the pressure of the blood is communicated through the aqueous solution and the air volume in the branch connection tubing to the pressure transducer unit, with the blood being spaced from the air volume. Preferably, substantially all of the branch connection tubing containing the aqueous solution and air volume has an inner diameter of substantially no more than 5 mm. This facilitates the continued separation of blood and solution when pressurized blood enters the branch connection tubing through the one end.

Arterial and venous blood pressures in hemodialysis and other extracorporeal tube sets have traditionally been measured indirectly via a blood/air interface and air column communicating with a pressure measuring transducer. Such interface is typically located in an air trap chamber. The air column typically is contained within and communicates between various components: the top of a chamber, a pressure monitor tube (PMT), a dialysis machine tubing and a pressure measuring transducer housing within the dialysis machine. Also known are blood/air interfaces without a chamber where a PMT communicates with a blood tube at a xe2x80x9cTxe2x80x9d connection.
Each air column typically comprises a sterile chamber/PMT portion and an unsterile machine portion. A sterility barrier (or transducer protector), capable of transmitting air pressure while maintaining sterility, separates the sterile chamber/PMT portion from each unsterile machine portion. Typically the sterility barrier is a hydrophobic membrane permeable to air flow but not to aqueous liquids. Typically, the air column has an large cross section in the air trap chamber (10-35 mm ID) and a narrow cross section in the PMT (0.5-3.5 mm ID).
Such blood/air interfaces have numerous problems. First, blood exposed to air activates a clotting cascade, usually in direct proportion to the blood/air interface surface area and to the degree of stagnation of the blood at the interface. Anticoagulants such as heparin are required to counteract such clotting tendency. Anticoagulants are costly and have numerous side effects for the patient.
Second, air in conventional air trap chambers can escape and enter the patient, even if no air enters the chamber in the incoming blood flow. That is, if and when the blood/air interface falls below the blood inlet (e.g., a downspout) the incoming blood flow causes cavitation at the interface and entrains air emboli in the downward blood flow, such that the air may escape the air trap chamber.
Third, air trap chambers often comprise over 20 percent of the size, weight and cost of the entire blood tubing set.
The fourth problem relates to blood/air interface level changes in the chamber due to pressure reductions (where liquid level goes down) and pressure increases (where liquid level goes up). Such level changes promote a risk of inhibiting accurate pressure measurements and may promote air emboli passing to the patient. The degree of blood/air interface level change is in direct proportion to the total volume of air in both the tube set and pressure machine portions according to Boyle""s law. Machine air volumes typically vary from 0.5 cc to more than 10 cc, depending on manufacturer and model. PMT air volumes typically range from 0.5 cc to 6 cc. Chamber air volumes depend on the blood level chosen by the clinician, but typically range from 3 cc to 20 cc. With the blood pump off, blood pressures are zero, and the arterial and venous blood/air interfaces are at the level in the chamber initially chosen by the clinician. But when blood flows increase to typical speeds (e.g. 450 ml/min with 15G AVF needles), pre-pump pressures drop as much as xe2x88x92400 mmHg or more and post-pump pressures increase as much as +500 mmHg.
In the positive pressure case, the air volume may be compressed as much as 40 percent or more ((1160 mmHg-760 mmHg)/760 mmHg). If the chamber/PMT air volume is less than 40 percent of the total air volume, the blood/air interface level can rise into the PMT until it is stopped by the transducer protector. Blood is thus trapped in the transducer protector and typically clots, and the machine transducer is no longer able to accurately measure pressure. This is a highly dangerous situation. In the negative pressure case, the air volume may be expanded as much as 65 percent or more (760 mmHg/(760 mmHg-300 mmHg)). If the chamber blood volume is less than the expansion air volume, the blood/air interface may fall until it empties the chamber and passes air to the patient, causing air emboli, an even more dangerous situation.
A fifth problem relates to dialysis tube sets and dialyzers requiring priming with physiologic fluid to eliminate unwanted air prior to processing blood through the circuit. In typical prior art chambers, an initial saline prime creates a saline/air interface in an upper portion of the chamber at a position chosen by the physician. When blood flow starts, however, saline is completely displaced by blood due to the excellent mixing in these chambers. Typically, the blood inlet is close to the saline/air interface or points at the saline/air interface. Thus, the saline/air interface quickly becomes a blood/air interface.
Other prior art chambers have long blood inlet downspouts or other arrangements to enter the chamber well below the fluid level in the chamber and pointed away from the fluid level. For example, Fresenius AG has an air trap chamber designed to promote a blood/saline or plasma/air interface with the blood inlet directed transversely and located well below the interface of the chamber. In these chambers, the initial saline/air interface may be set well above the blood inlet to the chamber. Blood is slightly heavier than saline (the cellular elements more so than plasma), so when blood enters the chamber (especially at low or moderate flow common in Europe and Japan), blood tends not to invade the stagnant (saline) area above the inlet level. This is often sufficient to stratify into a blood/saline/air interface or even stratify into a blood/plasma/air interface since plasma is almost the density of saline and will rise above blood""s cellular elements if relatively undisturbed. As saline-to-air contact initiates no clotting-cascade, and plasma-to-air contact has few if any initiators for clotting, this design is thought to provide clotting protection over a normal blood/air interface.
In practice, however, this approach has had little practical value. Dialysis has many events that cause abrupt pressure changes: peristaltic pump action at high flows (a large pressure pulse where flow instantaneously slows, stops or even reverses with each roller stroke); pump stoppages due to alarms; patient movements, patient coughing, line kinking, inadvertent clamping, etc. These pressure changes cause the fluid level to rise or fall rapidly. In those chambers which have large cross sectional areas, xe2x80x9cplug flowxe2x80x9d does not occur. Instead, blood xe2x80x9cburpsxe2x80x9d up into the stagnant plasma or saline layers, and displaces some or all of the plasma and/or saline. Now blood is in a stagnant area of the chamber with a blood/air interface, and significant clotting is created. xe2x80x9cPlug flowxe2x80x9d is the movement of two fluids in a tube as separate but intact bodies, such that an interface separating the two fluids is maintained. Plug flow is easier with relatively small ID tubes than larger tubes.
Sixth, a greater destroyer of a stable blood/plasma or saline interface in air trap chambers is air bubbles entrained in the incoming blood flow. These bubbles rise to the surface, passing through any saline or plasma layers because the cross sectional area of these chambers is much larger than the diameter of these bubbles. If bubbles enter a tube small enough that the bubble bridges from wall to wall, frictional forces stop the bubble from rising further, unless convective forces push on the fluid column. The bubble locks the fluid above the bubble from mixing with the fluid below the bubble (as artfully employed by clinical analyzers). Bubbles of less diameter than the tube they are carried in, however, will freely rise. Due to the non-airfoil shape of these bubbles, they drag up blood in their wake into the plasma/saline layers. It takes relatively few bubbles to completely displace essentially all plasma or saline with blood creating a stagnant blood/air interface. As above, this blood is now subject to the stagnation clotting cascade mechanism.
The prior art also includes Cobe machines that mate with a sterile cassette tube set with a non-porous, diaphragmatic sterility barrier mounted directly in an air trap chamber side wall, which eliminates the need for a pressure monitor tube. This set does, however, comprise a blood/air interface in the air trap chamber. Brugger et al U.S. Pat. No. 5,693,008 shows an arrangement of machine and tube set which eliminates the blood/air interface. Zanger U.S. Pat. No. 5,392,653 discloses blood pressure measurement without an blood/air interface, using a diaphragm in direct connection with a force transducer.
Another prior art of a Japanese company seeks to overcome the blood/air problem by interposing a low weight fat between the blood and air phases. It discloses injecting a low weight fat into each chamber. Because this fat""s density is significantly below that of blood or plasma, it floats on top and prevent a blood/air interface, and if the layer is disrupted by bubbles or pressure pulses, the fat again rises to become the air interface. It also claims that fat does not initiate any clotting cascade mechanism. The expense and pharmaceutical regulatory approval required of this approach has apparently prevented its use.
Worldwide, all hemodialysis machines in use today are designed for blood/air interface tube sets. These machines provide over 120 million dialyses per year for over 800,000 end stage renal disease patients. Recent disclosures of airless blood tubing sets will require new machines and many years to bring their benefits to a substantial number of patients. It is an objective of this invention to create tube sets and methods for all presently existing machines, and new machines, that eliminate the blood/air interface. It is also a preferred objective of this invention to reduce the amount of anticoagulant required to perform dialysis. It is a preferred objective of this invention to reduce clotting in the tube sets, putting the saline column at least partially in a tube that has an inner diameter that substantially promotes xe2x80x9cplug flowxe2x80x9d and keeps the saline in between the blood phase and the air phase. It is a preferred objective of this invention that no modification of the existing machines is required to use these tube sets and methods. Also by this invention, the number of tube set components can be reduced in number, size and cost.
By this invention, the blood/air interface can be eliminated while sensing pressure in blood flow tubing. The method comprises: placing an aqueous, typically physiological, isotonic, substantially cell-free solution, (typically normal medical saline solution or the like) into branch connection tubing that connects in branching relation with the blood flow tubing at one end, and connecting with a pressure transducer unit at its other end. An air volume is maintained to occupy a portion of the branch connection tubing which is adjacent to the other end near the pressure transducer unit. One then flows positively or negatively pressurized blood through the blood flow tubing. Thus, the pressure of the blood is communicated through the aqueous solution and then the air volume in the branch connection tubing to the pressure transducer unit, with the blood being spaced from the air volume.
Typically, substantially all of the branch connection tubing containing the aqueous solution and air volume has an inner diameter of substantially no more than 5 mm. One purpose of this is to facilitate continued separation of blood and the solution described above, when pressurized blood enters the branch connection tubing through the one end. Preferably, the inner diameter of the tubing will be substantially no more than 3.5 mm.
While the above facilitates the continued separation of blood and solution, a certain amount of mixing may take place in the branch connection tubing so that the aqueous, cell-free solution can become pink in the area adjacent to the blood-solution interface. For this and other reasons, it is preferred for a priming solution tube, which is connected to a source of priming solution, to be connected in branching relation with the branch connection tube. Thus, added portions of priming solution can be periodically added to push downwardly the aqueous solution in the branch connection tubing, which has become mixed with a small amount of blood, into the blood flow tubing during operation, so that the aqueous solution in the branch connection tubing can remain substantially blood cell-free.
In this invention, the blood/air interface of the prior art is thus replaced on a continuing basis by a blood/saline/air interface. A saline column (or other appropriate solution) is interposed during the priming procedure between the blood phase and the air phase. The saline column, saline/air interface and air column are located within the branch connection tubing communicating with a main blood flow tube, optionally with an enlarged chamber of the main blood flow tube. Preferably, such a blood chamber is filled completely (eliminating any blood/air interface), and is well mixed. Preferably, the branch connection tubing is sized to promote plug flow (so as to prevent the blood/saline interface from rapidly degrading with pressure pulses, alarms, patient movements and changes in blood pressure from atmospheric to operating pressures) and to resist free flow of air bubbles. Its inlet to the blood flow tubing may be positioned below the highest point in the chamber so as to resist entry of air bubbles.
The ratio of the saline volume in the chamber/PMT to the air volume in the system is sufficient to prevent transducer protectors of the pressure transducer unit from being wetted out in a positive pressure situation, or air being dumped into the main blood tube in a negative pressure situation. An in-line chamber maybe added to the branch connection tubing to help accomplish this.
This invention may use a variety of designs and methods, with and without air trap chambers in the blood tubing or in branch saline or air tubing.
The aqueous solution may be formulated to be compatible with blood to suppress clotting, for example, by the addition of heparin or the like. The heparin line which is conventionally found in extracorporeal blood sets may be connected in another branching connection to the branch connection tubing, typically at a connection downstream of a branch connection with the source of added aqueous solution, for priming and patient fluid maintenance.
The branch connection tubing may, if desired, define an in-line chamber that preferably extends for no more than 10 percent (and typically less than 7 percent) of the length of the branch connection tubing. The purpose of this is to provide an increased volume to the branch connection tubing, to reduce the movement of particularly the interface between blood and the aqueous solution as blood pressure changes.
Also, it may be desirable for the branch connection tubing to comprise a flow-resisting constriction to slow movement of the interface boundary between the blood and aqueous solution upon pressure changes. Particularly, the flow-resisting constriction is preferably positioned at a portion of the branch connection tubing that carries the aqueous solution, farther up the tubing than blood would be expected to travel. Thus, the movement of the interface boundary between the blood and the aqueous solution maybe slowed in a manner to reduce mixing of blood and solution at their interface in the event of large, sudden pressure changes. Preferably, the flow-resisting constriction is positioned at a portion of the branch connection tubing that carries the aqueous solution, to spare the blood from the stresses that might be encountered by passing through such restriction.
In another embodiment, the main blood flow tubing may comprise an enlarged chamber portion. The branch connection tube connects in branching relation with the blood flow tubing through a wall of the enlarged chamber portion. The enlarged chamber portion is preferably completely filled with aqueous solution at the end of priming of the set for use, and then it becomes completely filled with blood, except for air bubbles that may be trapped in the chamber during the use, and are periodically drawn away by a syringe through an injection site or branch tube, or through a hydrophobic vent, in conventional manner.
In this embodiment, the branch connection tube may have a proximal end portion which extends for a substantial distance into the enlarged chamber portion inwardly through its wall. In use, the interface boundary between the blood and aqueous fluid may occupy the proximal end portion.
The branch connection tube may be integral and nonseparable along its length from its connection to the main blood flow tubing, to the connector at its other end through which it connects with the pressure transducer unit. Alternatively, the branch connection tube may be separable into two or more serial components by means of a pair or pairs of engaging connectors in various ways as maybe desired. For example, the branch connection tube maybe separable by a pair of adjoining connectors positioned between a T- or Y-junction where a line to a source of priming solution connects with the branching tubing, and to the main blood tube, so that most of the branch connection tubing and its connected priming solution tube can be a separate set. Alternatively, the tube that connects between the priming solution and the branch connection tubing maybe a separate set, while the branch connection tubing is integral with the main blood tube. As another alternative, the branch connection tubing may carry an in-line chamber comprising preferably less than ten percent of the length of the branch connection tubing, and the line connected to the source of aqueous, cell-free solution (priming solution) can connect to that chamber in a form of a branch connection.
Branch connection tubings may connect to the blood tube both upstream (negative pressure) and downstream (positive pressure) of roller pump tubing, or other tubing which engages another type of pump for pumping through the tubing. Each of these branch connection tubings may communicate with a pressure transducer so that upstream and/or downstream pressure from the pump can be measured. The tubings will each have an air filled section adjacent the transducer protector and an aqueous solution-filled section adjacent the blood tube in accordance with this invention. Also, if desired, tubing may connect to each of these tubings in branching connection to provide access to a source of aqueous, isotonic, substantially cell-free solution (such as normal saline solution) so that such solution may be applied to the branch connection tubing. This solution may also be added back to the blood after treatment by hemofiltration for example, to give the patient a desired hematocrit in the blood before returning the blood to the patient.
The invention of this application may be utilized in the particular sets and the process of automatic priming thereof that fall under the scope of the invention as described in Utterberg U.S. patent application Ser. No. 08/954,804, filed Oct. 21, 1997, entitled xe2x80x9cAutomatic Priming of Blood Setsxe2x80x9d, now U.S. Pat. No. 5,951,870.
In another embodiment of this invention, an electronic transducer for pressure sensing can be dispensed with, and the pressure may be directly sensed by observing the behavior of a chamber or the interface between an aqueous solution-filled section and an air-filled section of the chamber of branch connection tubing, as more specifically described below.

Dialysis pressure monitoring with clot suppression


A foam reduction agent consisting of dibasic esters is shown and a process using a liquid contact with polystyrene foam wherein the higher boiling temperature of the dibasic esters and contact with the liquid provides a volume reduction process and less evaporation loss as well as safer transportation of the chemicals and the polystyrene in its reduced state. The resulting reduced sludge is also recyclable to superior quality raw polystyrene foam beads and the reduction agents are recoverable for future use. The resulting sludge also has unexpected beneficial uses hereto for unknown as a waterproofing agent.

This invention provides chemical agents to reduce polystyrene foam plastics to a compact form using a dibasic ester based chemical agent in liquid form which reduces the polystyrene foam to a sludge like material that is safe to ship and greatly reduces its volume of waste.
Polystyrene foam has been used for some time as packing material, insulation material, structural materials and other various uses. The foam has exhibited a great number of useful qualities in a great number of fields. The foams usefulness is based partly on its cost effectiveness, its inherent insulating qualities and easy of forming a great variety of shapes. For instance the food handling industry has found foam packaging to be of great use in the packaging of food products for its consumers. In addition, the building industry has found a great number of uses for the foam. The chief concern for the various uses of the foam has been the amount of waste that is generated by the use of foam products.
Generally speaking, polystyrene foam has caused great concern because of its lack of biodegradability. The foam by its nature takes up a great deal of volume per weight, which has cause many to question its overall usefulness when compared to the possible detrimental environmental impact. The environmental impact includes the accelerated rate that landfill space is being used up at because the foam, in its useful form, takes a great deal of space per weight of waste. Moreover, the transportation of the foam waste is very inefficient due to the volume weight ratio. Typically, the waste material is transported from a restaurant facility to a waste area. This transportation usually involves motor vehicle transport. The vehicles can transport a much greater weight of refuse than can be place in the vehicle due to the large volume the foam takes up. Therefore, the transportation is very inefficient wherein it does not utilize the capacity of the shipping means.
Also, in the industry it has been very difficult to find an effective method of recycling the foam products. This is due in part to the shipping cost described above and the cost of the process of the actual recycling. There is a need for a foam volume reduction method to allow use of more normal plastic recycle and processing equipment. At the present extra compaction steps and very expensive and specialized equipment is required to recycle polystyrene.
One approach to the recycling is to use chemicals to reduce the foam. The basic problem is that the chemicals that are obvious are very toxic to the environment and they are often banned by environmental legislation or regulations. One chemical series, pinene and terpenes such as d-limonene can reduce the foam volume. This approach is interesting but it fails to be an effective method in some cases. Specifically, the cost of d-limonene is directly related to the crop levels of citrus products. When there is a problem with the production of citrus products due to bad growing conditions it directly effects the price to recycle foam products to the point where it may no longer be cost effective.
Moreover, prior approaches evidence an inconsistent activity in collapsing foams that has not previously been addressed in the industry. While heat activation of the terpines has removed this problem (U.S. Pat. No. 5,223,543) it adds to the overall cost of recycling and it involves a volatile environmentally compromising chemical. The chemicals used in this patent were all a problem to ship due to their flash point. They are very volatile and therefore extra precaution has to be used when shipping such products that ultimately does not make it cost effective. The process also was basically vapor phase, providing for possible emissions of vapors which were a Clean Air Act Problem. Thus there is a major need for a foam reduction process that uses low volatility agents.
Also, the use of volatile chemicals presents another problem to the recycling efforts. The chemicals used heretofore would suffer great loss in the recycling process due to evaporation. This would make the recycling materials vary hard to recover to be used again in the recycling process. As such it would add a great deal of cost to the recycling efforts. The evaporated chemicals would also increase the danger of an accident during the recycling process due to unacceptable flash points in the chemicals. This is especially true were the chemicals best performance was aided by the addition of heat to the process. Ultimately, the volatile chemicals and heat required would lead to conditions during the recycling process that would be very dangerous.
An ideal process would have little need for heat activation (contra to U.S. Pat. No. 5,223,543) and would further allow viscous and higher boiling point materials to be used. Ideally, these materials would not require longer residence times prior to recycling. A long time would delay the sequence of breaking down the foam products and shipping of the same. This increase in residence times would add to the overall cost of the recycling process. Also, the need to decrease residence time must be balanced with reduced heat activation in combination with higher boiling point materials whose combination would result in a hereto for unobtainable efficient and safe reactant. In addition, it would be most desirable to have the product or sludge of the foam collapsing reactions that is safely shippable. This is accomplished by the present invention as further described herein. It would also be advantageous to identify effective compounds that insulate the foam reducer market from the wide price variation of the orange crop related d-limonene market.
Also, it would be desirable to have a compound that is environmentally friendly. Part of the major problem with the past use of foam products is that they now occupy a great deal of space in our landfills. Therefore, there is a significant need for an agent that can be used at these landfills on foam, which has already been deposited into landfills. The only way to accomplish this is by the application of a foam reducing agent that has no detrimental side effects on the environment.
This invention reveals a method to provide rapid destruction of the cells of polystyrene foams by use of a combination of specific chemicals of the class of aliphatic dibasic esters, either alone or with other foam reduction agents and surfactants that are active and which readily attack, with no or little heat activation, polystyrene foam and allows easy recycling. The easy recycling is due to reduced bulk and ease of storage of the collapsed polystyrene foam in sludge foam, ease of processing, and economical transportation prior to recycling. The process involves the exposure of said foams to liquid sprays of specific esters, which have a relatively high boiling point and may be easily and safely transported.
This invention solves the volume problem of polystyrene foam materials and allows the easy and inexpensive shipment of the foam materials after cost effective reduction in volume by use of liquid aliphatic dibasic esters. These materials such as dimethyl glutarate, dimethyl adipate and dimethyl succinate are all effective foam reduction agents. While they have activity individually, as mixtures the action is especially favorable. Moreover, with the addition of small amounts of heat to the process the overall effectiveness is increased while having little effect on the cost of recycling. Also, because of the reactants lower boiling points not much reactant is lost in the heating process. The lower boiling points and benign nature of the reactants makes the reactant process safer than know chemical reactants with highly boiling points.
The use of active chemicals assists in making foamed polystyrene materials easier to incinerate or reprocess. The product of this process and method is solvatable and can be made pumpable and can then be filtered and reprocessed or injected into the furnaces where the high fuel value of the material offers energy savings. If filtered and recycled, high quality polystyrene raw material bead product can be made. Heretofore it has been impossible to cost effectively recycle polystyrene high quality raw material. High quality recycling is important in polystyrene recycling where the recycled product is desirable to be used in the food packing industry. The food packing industry has strict requirements for parts per million of contaminant in the styrene used. The process disclosed herein is the only knows recycling that is cost effective and yields recycled material that would meet the requirements of the food packing industry.
The process of volume reduction has been hampered by high loss due to evaporation. This invention helps cure this problem by discovery of agents with high boiling points, which effect foam reduction in the liquid state with little or no heat added.
The materials used in this method of volume reduction are also recoverable by removal in the recycling process and the majority of compounds used can be easily separated from moisture and volatile organic by a combination of decanting, mutual solubility with other organic compounds and thermal stripping.
The materials are further environmentally nontoxic.
The invention started with identification of the unexpected affinity of the vapors of certain solvents found in perfumes. Identification of the active agent in the process became the key to the initial foam volume reduction process. This material identified was d-limonene. D-limonene vapors acted upon the foam and rapidly reduced the volume. The sorption process, when there was sufficient vapor present, was one that continued until the foam was reduced to a viscous liquid. This aggressive mutual solubility was relatively fast as long as there is a presence of the needed vapors.
This invention furthers the concept of foam reduction by the discovery of a set of chemicals which are as effective as the vapor process noted with d-limonene but which work in a liquid state and thus avoids the need for a vapor saturated atmosphere around the collapsing foam.
The process in this invention would still be a curiosity if the solvents used were some of the common materials such as acetones, methylene chlorides or other relatively toxic compounds. It was known that these strong solvents were effective in dissolving polystyrene foams. Early work assumed key requirements were the relatively high vapor pressure of d-limonene since this chemical and the other known active solvents that were relatively toxic all had high vapor pressures. It was thus assumed at earlier points in the research, that the key conditions were the presence of an active vapor and polystyrene foams. The volatile oils which were the key solvents in earlier work all had relatively low boiling points and thus to make the process effective, restriction of the vapor must also be present. A result was relatively large loss to the atmosphere and the resulting lessening cost effectiveness of the chemical due to this evaporation and vapor loss. This invention discloses a new series of chemicals that have not previously been considered for this purpose since they are not easy to use in the vapor phase. These new dibasic ester uses eliminate much of the loss and further improves fire safety of the recycling or foam reduction process. The extra factor is the removal of the vapor requirement with discovery of liquid phase foam reduction agents.
The formulas used for this invention consist of esters, specifically dibasic esters. These esters, especially the aliphatic dibasic esters such as dimethyl glutarate, dimethyl adipate, and dimethyl succinate (CAS,#119-40-0; 627-93-0; 106-65-0) have rapid reaction with polystyrene foams, again acting as a stress cracking agent to destroy the cell wall webs which are highly stressed, then destroying the inter cellular structure that remains. In addition, through the experimentation that is the subject of the invention disclosed herein it was learned that esters themselves were effectives reactants when small amounts of heat were added to the process. Esters have been disclosed in a U.S. patent to Shiino et al. U.S. Pat. No. 5,629,352. However, that disclosure did not teach or contemplate heating. The addition of small amounts of heat to the ester prior to use as a reactant greatly increases is reactant characteristics. The presence of ester without heat will reduce foam but in a time period that is not efficient for recycling purposes.
The dibasic esters disclosed above are not like the vapor processes used previously for foam reduction, which attack foam by dissolving the foam in the vapors of natural organic compounds. The present chemicals act as liquids. They have boiling points of 196 to 225 degrees C. with a vapor pressure of only 0.2 mm Hg at 20 degrees C. They have an evaporation rate one tenth that of butyl acetate, a common reference. The specific gravity is slightly greater that water and mutual solubility is limited, allowing easy separation from water mixes. The dibasic esters also have low solubility in water and very high solubility in many alcohols so that separation schemes for recovery of the dibasic mix is feasible. The use of the dibasic esters, especially as a mixture, eliminates the large loss due to evaporation of the d-limonene used as the reducing agent in previous reduction and recovery methods. The evaporation of active agents had previously made the process partly ineffective in many applications because of cost. The present invention is cost effective since this loss is very low.
The active agents also have several key property needs. Since they will be going into dumps and trash, they must be environmentally sound. Ideally, they should not be within a range of boiling points and vapor pressures that will either immediately flash off or will over time evaporate to form a vapor layer within a landfill. Looking at solvents, which attack polystyrene foams, nearly all are environmental problem chemicals. One class of chemicals broadly noted as isoprenoid and terpene compounds contain mostly environmentally safe naturally derived compounds, but most of these compounds are relatively volatile and would at least form a vapor layer in a dump situation. The dibasic esters of this invention are of sufficiently low volatility that they do not form an indump layer. This removes future problems of large vapor escape if the dump top impermeable layers are destroyed or damaged by man made or natural phenomena such as earthquakes.
In patents on activation (U.S. Pat. 5,223,543) the emphasis was on d-limonene. This was selected for cost and volatility reasons since prior uses relied on rapid action due to application in exposed areas as activated liquid. The use of a variety of liquid volatilities as long as vapor is generated over an extended time ranging from several hours to several days is also covered. The present use of esters with small amounts of heat, dibasic esters, and d-limonene in combination with esters and dibasic esters, as foam reduction agents is also effective. The present invention is superior in creating a vast reduction in the vapor loss, in preventing vapor layers within disposal dumps, in reduction of loss in reprocessing operations, which are typically at temperatures of over 270 degrees C. Also, the present invention limits reliance on d-limonene, which is can experience unstable pricing and is not easily reclaimed after recycling.
Finally, all of the contemplated reactants described herein may be optionally aided in their reactant effectiveness by including in the reactant process a pretreatment shredding of the polystyrene. The shredding can be effectively accomplished through the use of a hopper that shreds the polystyrene in the first stage of the process. The second stage of the process would have the shredded polystyrene being treaded with one of the disclosed reactants in a holding compartment of the hopper. The resultant foam sludge could then be pumped from the hopper to containers for transportation to waste or recycling locations.
There are no drawings with this application.

Reduction in polystyrene foams with dibasic esters