TWI353853B - Method and compositions empolying formulations of - Google Patents

Description

1353853 VI. INSTRUCTIONS: RELATED APPLICATIONS - This application is a priority to request the serial number of a US patent application. TECHNICAL FIELD OF THE INVENTION The present invention relates to a unique composition comprising a biocompatible oil and a non-steroidal anti-inflammatory drug (NS AID) which is effective to reduce φ NSAID (non-steroid anti-inflammatory) Gastrointestinal toxicity and enhancement of drug treatment for inflammation, pain, fever and thrombosis and other diseases such as: stroke, traumatic brain injury, spinal cord injury, cardiovascular disease, ovarian cancer, colon cancer, Alzheimer's disease, arthritis , uveitis, and mucositis and other medical activities. In particular, the compounds of the present invention relate to a composition wherein the NS AID (non-steroidal anti-inflammatory drug) is mixed in a powder form into a biocompatible oil comprising a phospholipid to form a medicament, and the agent may be a solution, a paste, A semi-solid, dispersion, suspension, colloid or mixture thereof and the agent φ can be administered internally, orally and/or topically. [Prior Art] NSAID (non-steroidal anti-inflammatory drugs) constitutes a compound group, first discovered as aspirin, which has the ability to inhibit some biological pathogenic processes «including: fever, pain, thrombosis and cancer formation . 1 As a direct result of this significant medical benefit, NSAID S (non-steroidal anti-inflammatory drugs) is consumed in large quantities by non-prescribing or prescription drugs. Because of this significant use, a significant percentage of Chinese people regularly consume NSAIDS (non-steroidal anti-inflammatory [-5- 1353853 inflammatory drugs]: 30 to 40 million Americans suffering from rheumatoid or osteoarthritis; and Countless others who take medication to treat or prevent: inflammation and pain caused by other inflammatory conditions or injuries, menstrual pain; fever; development of thrombosis and related cardiovascular diseases; ovarian cancer, colon cancer and AIDS Haimo's disease. The use of hMS AID (non-steroidal anti-inflammatory drugs) has always been increasing, especially in the elderly, the problem is that these drugs often induce gastrointestinal side effects. 3·6 These drugs in some individuals' stomach and intestines Causes indigestion (stomach pain, heartburn, bloating or nausea), erosion, gastritis/duodenal inflammation and ulcers. Gastrointestinal bleeding is likely to occur in NSAID (non-steroidal anti-inflammatory drugs) users leading to anemia (various severity), or bleeding - which can be life-threatening in most serious cases. 7,8 – or more of these complications have been estimated to occur in 20-40% of regular NSAID users. Through the extensive sales of NS AID, even the infrequent gastrointestinal complication forces an estimated 76,000 Americans to the hospital each year and an estimated 7,600 deaths. One of the major contributions to the understanding of NSAIDs was the pioneering study of Vane and associates from the early 1970s, which reported that chemically distinct members of the NS AID population shared inhibitory enzymes, cyclooxygenase (COX) activity. The ability of this cyclooxygenase (COX) to catalyze the conversion of arachidonic acid to prostaglandin 2 and Hz by successive steps of oxidation and peroxidation. 9.11 Prostaglandin H2 is then converted to one of the carbonic acid by a method catalyzed by a specific prostaglandin synthase in the target cells. Therefore, by reversible or irreversible inhibition of cyclooxygenase (COX) activity, NSAID can be 1353853

Depletion of specific tissues or cellular fluids of prostaglandins that have been shown to contribute to tissue inflammation. 12 Shortly after these findings, Robert and his associates of Upjohn confirmed that some classes of prostaglandins shared protection against gastrointestinal epithelial stimuli, which were confirmed by some of the properties of ulcerative compounds and/or conditions. The "cytoprotective" properties of these fat-promoting agents. Based on these two important contributions, it is concluded that N SAIDS (non-steroidal anti-inflammatory drugs) induces gastrointestinal epithelial damage by inhibiting mucosal COX activity and depleting the "cytoprotective" prostaglandin group. And ulcers. The next and recent developments that we have learned are from the early 1990s, when some researchers studied and identified the second COX isozyme (now called COX-2). It is structurally and functionally related to the enzyme originally described (now called C0X-1). Unlike COX-1, which is expressed in most tissues including gastrointestinal mucosa, COX-2 has been shown to be primarily induced by cytokines and other contributing agents of inflammation. Based on these findings, coupled with the evidence that C0X-2 can selectively exhibit φ at the site of inflammation and low or no detectable sputum in the uninflamed gastrointestinal mucosa, 19_23 some pharmaceutical institutions have begun to develop. A compound that selectively inhibits COX-2. Efforts have been made to develop the first two C0X-2 selective inhibitors, Celebrex KCelecoxib and Vioxx (Rofecoxib). The preclinical and clinical data published to date indicate that these compounds are therapeutically effective and have low toxicity to the gastrointestinal mucosa. This message is very exciting for the public and the public, so the first two years of sale of Celebrex and Vioxx have become the record of breaking record 1353853.

The present inventors and some investigators who are concerned with nsaid-induced gastrointestinal injury are mainly concerned that the association between COX inhibition and gastrointestinal damage and bleeding is not extremely strong. For example, Ligumsy and his associates published a series of papers on rats and dogs in the early 1980s, which appeared to separate COX inhibition from gastrointestinal injury. 25·27 They initially confirmed aspirin and its metabolites, salicylic acid has the same ability to induce canine gastric mucosal damage, even if aspirin depletes the "cytoprotective" prostaglandin tissue, and salicylic acid The COX inhibitory activity was not observed. 25 In the subsequent rodent study, it was confirmed that subcutaneous or intragastric administration of aspirin was ignored, and mucosal COX activity was inhibited by 90%, whereas ulcers were only when NS AID was from the stomach. It is formed in the stomach of the mouse when it is administered internally. 26'27 Whittle also reported the effect of indomethacin on COX inhibition and mucosal damage in the small intestine, as the small intestine lesions began to develop only 48 hours after the administration of NS AID, at this point COX The activity (usually completely inhibited within 3 hours (<3 hours) of administration of anti-inflammatory niacin) has returned to normal. 28 It must be noted that the evidence that mucosal COX inhibition is not directly involved in NSAID-induced bowel disease is also confirmed by some clinical studies. These clinical studies have reported that, unlike oral NS AID, intravenous injection Taking aspirin does not cause detectable histological damage to the human gastric mucosa. 29 It is also reported that after 2-4 hours of NSAID treatment, human gastric mucosa becomes resistant to oral aspirin or anti-inflammatory citrate, and this adaptive response remains completely blocked during the study period. The recovery of COX activity is irrelevant. 3<) -8- 1353853 Finally, because NSAID mainly induces gastrointestinal injury by inhibiting mucosal C0X-1, it is predicted that the squirrel lacking this isozyme is due to the standard base-* Splitting, there will be a tendency to develop into a spontaneous mucosal ulcer and it is wild, and the type of litter is more sensitive to NS AID. Langenbach and his associates 31 reported that animals without COX-1 did not have detectable gastrointestinal disorders and, if distinguished, were more resistant to the development of anti-inflammatory citrate-induced ulcers. To make things more complicated, Morham et al. 32 continued to study φ. The report pointed out that COX-2 knockout mice cannot survive and often die from peritonitis and kidney disease. The possibility that COX-2 inhibition may be harmful is also supported by some animal studies. These studies indicate that if the animal is treated with a selective COX-2 blocker, the recovery of the proximal and distal intestinal ulcers will deterioration. A similar incidence of 33'34 humans has not been reported so far. Based on the evidence provided above, a case can be made to investigate other mechanisms of NS AIDS (non-steroidal anti-inflammatory drugs) to induce gastrointestinal mucosal damage, and to investigate how this information can be used to develop or reduce these deficiencies. Other strategies for gastrointestinal toxicity. Other potential targets for NSAID-induced gastro-intestinal disease - reduce mucosal blood flow and induce leukocyte adhesion to the vessel wall; unwind oxidative phosphorylation; induce cellular acidification due to proton characteristics; and attenuate mucosal Hydrophobic, non-wettable properties, thus increasing the tissue's ability to be sensitive to luminol. 35_4<) This latter nature is the focus of the inventor's laboratory over the past 15 years. In the year of 1999, the inventors' laboratory first observed that the dog's stomach mucosa was detected by contact angle analysis to have a unique hydrophobic surface. 4 1,42 Since then, he and his laboratory have confirmed that the non-wettable surface properties of the gastric mucosa -9- 1353853 are found in other species including rodents and humans. 4<)'43'44 In addition, biochemical and morphological techniques are used to demonstrate that this property is attributable to the extracellular lining of surface activator phospholipids within the mucus layer and in the cladding. 45_47 The inventors' laboratory also observed that many agents that destroy the gastric mucosa, including NSAIDS (non-steroidal anti-inflammatory drugs), have the ability to transform tissue from non-wettable (hydrophobic) to wettable (hydrophilic) state. Ability, and this damage can be attenuated by administering synthetic or purified phospholipids. 48_51

In recent years, research has focused on the movement of NSAID-phospholipid interactions. Evidence that these studies have been judged is that NS AIDS (non-steroidal anti-inflammatory drugs) can be used with zwitterionic phospholipids, such as phospholipid choline (PC) on and in the mucus layer The zwitterionic phospholipid, the positively charged choline head group of phospholipid choline (PC) and the electrostatic binding site between the negative charge (carboxy or sulfonate) group of NSAID chemically associate to induce gastrointestinal damage. 52 Based on this information, our team estimates the gastrointestinal toxicity of NSAIDS (non-steroidal anti-inflammatory drugs) that have been chemically pre-associated with synthetic or purified phosphocholine before administration. The evidence is that these The novel drugs are far less harmful than the unmodified NSAIDS in terms of gastrointestinal lesion formation and bleeding in mice. The applicability of this method to human diseases has recently been shown to be a phospholipid choline-aspirin in the current clinical trial, using purified (93% pure) phosphocholine, during the 4-day period, in front-end double-blind, The number of gastric lesions in humans induced by crossover studies was significantly less than that of unmodified aspirin. 53 Interestingly, the inventors' laboratory also found that phospholipid choline-non-steroidal anti-inflammatory drugs (PC-NSAID) have an animal model of fever, inflammation/pain, thrombosis and -10-13553 osteoporosis. Compared with the efficacy and efficacy of unmodified drugs, it can be seen that their lower gastric toxicity cannot be explained simply by the decrease in bioavailability. 5 2,5 4 - * Although phospholipid choline (other phospholipids) and non-steroidal anti-inflammatory drugs (NSAIDS) can reduce the pathogenic effect of NSAID administration, oral administration of these pharmaceutical combinations is definitely not enough because Each pharmaceutical combination requires a greater amount than the NSAID alone. Therefore, the NSAID and the φ composition of the carrier are required in the art to increase the concentration of the NSAID in the composition and the carrier therein can reduce the pathogenic effect of the non-steroidal anti-inflammatory drug (NSAIDS) and the composition is suitable for oral, internal Or a form of partial persuasion. Moreover, there is a need in the art for an improved self-expiration period, particularly for NSAID compositions for use in pharmaceuticals containing aspirin. SUMMARY OF THE INVENTION Summary of the Invention φ General Composition The present invention provides a composition comprising a relatively high concentration of a non-steroidal anti-inflammatory drug (NSAID) in a non-aqueous, mobile carrier. The present invention provides an NSAID composition in a non-aqueous, flowable carrier wherein the carrier is a biocompatible oil and a phospholipid. The present invention provides an NSAID composition in a non-aqueous, flowable carrier wherein the carrier is a phospholipid-rich biocompatible oil. The present invention also provides a composition comprising a relatively high concentration of NSAID in a non-aqueous, mobile carrier, wherein the carrier or its constituent is a biological agent that reduces the pathogenic effect of the NSAID by increasing the pathogenic effect of the NSAID [ -11 - 1353853 Availability, and increased availability of NS AID across the relatively hydrophobic barrier of animals including humans.

The present invention also provides a composition comprising a relatively high concentration of NSAID in a non-aqueous, flowing carrier, a phospholipid wherein the phospholipid is sufficient to reduce the pathogenic effect of the NSAID, increase the bioavailability of the NSAID, and increase the NSAID The amount of availability across the animal, including the relatively hydrophobic barrier of humans, exists. The present invention provides a composition comprising a relatively high concentration of NSAID in a non-aqueous, flowable carrier comprising a phospholipid and a biocompatible oil, wherein the phospholipid is sufficient to reduce the pathogenic effect of the NSAID, increasing the NSAID Bioavailability, and the amount by which the NSAID increases across the availability of relatively hydrophobic barriers in animals, including humans, exists.

The presence of phospholipids also reduces the general pathogenicity and toxicity of NSAIDs. Therefore, phospholipids can reduce and/or prevent liver damage caused by administration of acetaminophen and/or inhibition by other non-steroidal anti-inflammatory drugs (NSAID S) such as ibuprofen or COX-2. Kidney and/or cardiovascular side effects caused by the agent. General Process for General Compositions The present invention also provides a process for preparing a composition comprising an NSAID in a non-aqueous, flowable carrier comprising combining an NSAID with a carrier to form a solution, paste, semi-solid, dispersion, suspension The step of a liquid, a colloidal suspension or a mixture thereof. -12- 1353853 The present invention also provides a method of preparing a composition comprising an NSAID in a non-aqueous, flowable carrier comprising a phospholipid comprising combining an NSAID with a carrier to form a phospholipid-NSAID associative complex. The steps of solution, paste, .* semi-solid, dispersion, suspension, colloidal suspension or mixtures thereof. The invention also provides a method of preparing a composition comprising an NSAID in a non-aqueous, flowable carrier comprising a phospholipid choline-containing biocompatible oil, comprising combining an NSAID with a carrier to form a phospholipid-containing A step of a solution, paste, semi-solid, dispersion, suspension, colloidal suspension or mixture of NSAID associative complexes. The invention also provides a method of preparing a composition comprising an NSAID in a non-aqueous, flowable carrier comprising combining an NSAID with a carrier to form a solution, paste, semi-solid, dispersion, suspension, colloidal suspension or A step of the mixture thereof, and wherein the carrier comprises a phospholipid-containing biocompatible oil and a phospholipid or a mixture thereof. ·

Emulsified Composition The present invention also provides an aqueous emulsion comprising a composition of a non-aqueous carrier, wherein the carrier comprises a biocompatible oil, a phospholipid sufficient to produce a medically beneficial effect, and a zero to effective medical amount of NSAID and when the NSAID is present, the phospholipid The amount is also sufficient to reduce the pathogenic effect of NSAID. The aqueous emulsion may also include a biocompatible emulsifier to maintain the composition in an emulsion state for a prolonged period of time. The particle size of the emulsified composition is preferably small enough to allow the composition to be orally ingested or injected into a tissue or organ site without causing adverse effects. Microemulsions are preferred for intravenous or intra-arterial injection, and the particle size can be reduced to between 0.5 and about 10 microns, preferably between about 1 and 5 microns.

The invention also provides an aqueous microemulsion comprising a composition of a non-aqueous carrier, wherein the carrier comprises a biocompatible oil, a phospholipid sufficient to produce a medically beneficial effect, and a zero to effective medical amount of NSAID and the amount of phospholipid when the NSAID is present It is also sufficient to reduce the pathogenic effect of NS AID. The aqueous emulsion may also include a biocompatible emulsifier to maintain the composition in an emulsion state for a prolonged period of time. Method for preparing emulsified composition

The invention also provides a process for the preparation of an aqueous emulsion according to the invention, which comprises adding a predetermined amount of the desired non-aqueous composition of the invention to an aqueous solution in the absence or presence of an emulsifier, and mixing the composition with the solution for a period of time sufficient to form an emulsion. The step of time wherein the emulsifier, when present, is present in an amount sufficient to form a stable emulsion. The invention also provides a process for preparing an aqueous microemulsion according to the invention, which comprises adding a predetermined amount of the desired non-aqueous composition of the invention to an aqueous solution in the absence or presence of an emulsifier, and then mixing the composition with the solution for a sufficient amount to form an emulsion. The time is then followed by shearing the emulsion in a microemulsified condition to form a microemulsion wherein the emulsifier, when present, is present in an amount sufficient to form a stable microemulsion. The reason why the emulsifier is not necessary is because the phospholipid itself has some emulsifying properties. -14- 1353853 Composition for treating inflammation The present invention also provides a composition for reducing tissue inflammation comprising a non-aqueous carrier and the non-aqueous carrier comprising an effective medical amount of NS AID and a sufficient amount to reduce the pathogenic effect of NS AID Phospholipids, wherein the composition reduces the inflammation of the tissue at a dose of NSAID which is generally lower than the dose required to initiate the same medical response in the absence of phospholipids, while reducing mucosal toxicity and/or irritation.

The invention also provides post-operative treatment to reduce inflammation of tissues, organs and/or incisions and other results, wherein the composition comprises a non-aqueous carrier and the non-aqueous carrier comprises an effective medical amount of NSAID and a sufficient amount to reduce the pathogenic effect of NSAID. a phospholipid, or a composition thereof comprising an aqueous solvent (e.g., an emulsion or a microemulsion) having a non-aqueous carrier composition dispersed therein, wherein the composition is less than the dose of NSAID required to initiate the same medical response in the absence of phospholipid deficiency. Reduces inflammation of the tissue while reducing mucosal toxicity and/or irritation. Of course, the composition may be an ointment, sprayed, coated on a coating, coated on a biodegradable substrate, or the like. Composition for treating platelet aggregation The present invention also provides a composition for reducing platelet aggregation, wherein the composition comprises a non-aqueous carrier and the non-aqueous carrier comprises an effective medical amount of NSAID and a sufficient amount of phospholipid which reduces the pathogenic effect of NSAID 'or wherein the composition comprises an aqueous solvent (e.g., an emulsion or microemulsion) having a non-aqueous carrier composition dispersed therein, wherein the composition lowers blood at a dose lower than the dose required for the same medical response, which is generally lower than the phospholipid deficiency. [S 3 -15- 1353853 Small plate assembly, while reducing mucosal toxicity and / or irritation. Composition for treating fever

The present invention also provides a composition having anti-pyrogenic activity, wherein the composition comprises a non-aqueous carrier and the non-aqueous carrier comprises an effective medical amount of NSAID and a sufficient amount of phospholipid which can reduce the pathogenic effect of NSAID, or wherein the composition includes non-aqueous An aqueous solvent (for example, an emulsion or a microemulsion) in which the aqueous carrier composition is dispersed, wherein the composition has an anti-pyrogenic activity at a dose lower than the dose required for the same medical reaction at a dose lower than the phospholipid deficiency, and at the same time reduces mucosal toxicity and / or irritating" for the treatment of ulcer tissue components

The invention also provides a composition for treating ulcerated tissue, wherein the composition comprises an aqueous emulsion or microemulsion comprising a phospholipid, a biocompatible oil and a zero to effective medical amount NSAID, or the composition comprises a phospholipid, biocompatible Sexual oil and a non-aqueous composition of zero to effective medical amount NSAID wherein the phospholipid is present in an amount sufficient to reduce tissue ulceration and the NSAID, when present, reduces inflammation of the tissue ulcer area. Composition for treating oral ulcers The present invention also provides a mouthwash comprising an aqueous emulsion or microemulsion comprising a phospholipid, a biocompatible oil and a zero to effective medical amount NSAID, wherein the phospholipid is sufficient to reduce mouth ulcers The amount present and the NSAID, when present, can reduce the inflammation of the oral ulcer area and the amount of phospholipids is not only sufficient to reduce the oral ulcers by -1,353,853, but also to reduce the NSAID-induced tissue damage when present. · Composition for treating oral, esophageal and gastrointestinal ulcers The present invention also provides a pillable medicament comprising an aqueous emulsion or microemulsion comprising a phospholipid biocompatible oil and a zero to effective medical amount NS AID, Wherein the phospholipid is present in an amount sufficient to reduce the mouth, esophagus and/or gastrointestinal ulcers and the NSAID, when present, reduces inflammation of the oral, esophageal and/or gastrointestinal ulcer areas, and the amount of phospholipid is not only sufficient Lowering the mouth, esophagus and gastrointestinal ulcers is also sufficient to reduce NSAID-induced tissue damage when present. Composition for treating ocular inflammation The present invention also provides an eye drop comprising a phosphorus emulsion, a biocompatible oil and a zero-effective medical amount NSAID aqueous emulsion or microemulsion, which is contained in an aqueous solution. Wherein the phospholipid is present in an amount sufficient to reduce inflammation and/or ulceration or irritation of the eye and the NSAID, when present, reduces inflammation of the ocular sclera, uveal, lens or choroid-retinal region, and phosphorus-lipid The amount is not only sufficient to reduce inflammation of the eye, but is also sufficient to reduce NSAID-induced tissue damage when present. Method of Treating Ulcer Tissues The present invention also provides a method for treating oral, esophageal, gastrointestinal tract' and/or ocular inflammation and/or ulceration conditions by administering the emulsion or microemulsion of the present invention [S1-17-1353853 method. Composition for treating central and/or peripheral nervous system trauma

The invention also provides a composition for oral or internal treatment of spinal cord, stroke and/or traumatic brain injury, wherein the composition comprises a non-aqueous carrier containing a phospholipid and an effective medical amount NS AID or a composition comprising a phospholipid, a biocompatible phase Capacitive oils and non-aqueous compositions of zero-effective medical dose NS AID, in which phospholipids can be increased · N SAID transport to cross the blood-brain barrier or to the central nervous system (CNS) or peripheral nervous system (PNS) to Many NSAIDs reach the location of the trauma and reduce inflammation, which reduces inflammation, platelet aggregation, pain (receptive) sensation, cell death and/or apoptosis due to inflammation. Method for treating central and/or peripheral nervous system trauma

The invention also provides a method for treating spinal cord, stroke and/or traumatic brain injury by directly administering the composition of the invention by oral or by injection, wherein the direct administration method can be intravenous (intravenous administration), artery (intra-arterial administration) or directly to the trauma site (direct administration), when administered intravenously or intra-arterially, phospholipids can increase NSAID delivery to cross the blood-brain barrier to allow more NSAIDs to reach the site of trauma and Reduces inflammation and phospholipids reduce the pathogenic effects of NSAIDs in all forms of administration. The present invention also provides an agent for ameliorating the symptoms of spinal cord injury (chronic pain syndrome), stroke and/or traumatic brain injury, wherein the agent is an aqueous emulsion or a microemulsion comprising a relatively high concentration of NSAID on an oil base -18- In a carrier containing phospholipids of 1353853, wherein the NSAID and the phospholipid form a form of an associative complex in the agent, wherein the composition comprises a sufficient concentration of NSAID to reduce swelling of the wound tissue and to reduce the concentration of phospholipids to reduce The pathogenic effect of NSAID on traumatic tissue. Composition for treating Alzheimer's disease The present invention also provides a composition for preventing, treating or ameliorating symptoms associated with Alzheimer's disease, including biocompatible oils, phospholipids and effective medical treatment The amount of NSAID, in which NSAIDs and phospholipids are used to prevent the onset of symptoms of Alzheimer's disease or to improve the symptoms of Alzheimer's disease. Method for treating Alzheimer's disease The present invention also provides a method for preventing, treating or ameliorating symptoms associated with Alzheimer's disease, which comprises administering the composition of the present invention to a mouth according to the present invention and/or The steps of internal investment.

Definitions of nouns The following nouns have the following definitions, which may or may not correspond to their generally accepted definitions: The so-called "NSAID" means any of a variety of drugs generally classified as non-steroidal anti-inflammatory drugs, including , but not limited to, Ibuprofen, piroxicam, salicylate aspirin, naproxen, indomethacin 'C0X2 inhibitor or any mixture thereof. -19- 1353853 By "substantially free", it is meant that the amount of a given ingredient included in the composition is biologically inert and/or inactive, and preferably, the component is intended to be less than about 〇.1% by weight. It is preferred that the amount of the ingredients, especially less than about 0.01% by weight, be present. By "relatively high concentration" is meant a weight ratio of NSAID to carrier of from about 10:1 to about 1:10. The weight ratio of N SAID to carrier is preferably from about 5:1 to about 1:5, especially from about 2:1 to about 1:2, and especially from about 2:1 to about

The so-called zwitterionic phospholipids cover a wide range of phospholipids including, but not limited to, phospholipids, phospholipids, phospholipids, sphingomyelins and other neuroketamines, as well as a variety of other zwitterionic phospholipids. By "biocompatible oil" is meant any oil approved by the Food and Drug Administration (FDA) for human consumption or for consumption by an animal. By "internal administration" or "internal administration" is meant the administration of a technique that can present a composition to the bloodstream, tissue, or organ without first passing through the digestive tract. % The so-called "oral" or "oral orally" means that it is administered through the mouth. By "locally administered" or "locally administered" is meant to be administered to a surface, such as a skin wide, a mucous membrane, an eye, a tissue or organ exposed during a surgical procedure, or any other exposure. Body tissue. _ "Associative Complex" means a non-covalent chemical and/or physical interaction between an NSAID and a phospholipid such as an interaction between an NSAID and a zwitterionic phospholipid. By "sexionic" it is meant a molecule comprising a positively charged -20- 1353853 charge and a negatively charged functional group under biological acid and alkali hydrazine. By "anionic phospholipid" is meant all of the negatively charged phospholipids under the biological acid and alkali. . . . "Neutral fat" means fat without charge. By "emulsion" is meant a suspension in which the immiscible phase is suspended in another immiscible phase, the first phase in the form of droplets being suspended in the second phase. As used herein, so-called emulsions include suspensions which can be separated quickly or not at all, and thus include stability and restless emulsions. By "stabilized emulsion" is meant an oil-in-water mixture which does not separate at least one day after preparation, preferably at least one week without separation, especially at least one month without separation and in particular indefinitely maintaining the emulsion state. By "stabilized microemulsion" is meant an oil-in-water mixture which does not separate for at least one day after preparation, preferably at least one week without separation, especially at least one month without separation and in particular indefinitely maintaining the emulsion state. By "relatively hydrophobic barrier" is meant an exterior having hydrophobic properties, Φ internal, cell or cell barrier, which generally resists or reduces the transport of hydrophilic agents across the barrier. Such barriers include mucosal gel layers, serosal membranes (cell membranes), blood-brain barriers, or any barriers to animals, including humans, which are more likely to transport hydrophobic materials than by transporting hydrophilic materials. DETAILED DESCRIPTION OF THE INVENTION The present inventors have discovered that a non-aqueous, flowable biocompatible carrier comprising a phospholipid and any NSAID (non-steroidal anti-inflammatory-21-1353853 drug) unique pharmaceutical composition It can be prepared to accelerate the repair of mucosal tissue ulcers and/or reduce the pathogenic effect of NSAID (non-steroidal anti-inflammatory drugs). When the NSAID is present, the weight ratio of NSAID to carrier typically ranges from about 10:1 to 1:10, which results in a highly concentrated NSAID in a mixture in the carrier with surprisingly low gastrointestinal toxicity and enhanced NSAID efficacy. . The weight ratio of NSAID to carrier is preferably from about 5:1 to 1:5, especially from about 2:1 to 1:2, and especially from about 2:1 to 1:1.

In terms of a composition comprising an NSAID, the present invention has been practiced in a rodent model of NSAID-induced ulcer disease and acute inflammation of the hind paw. The composition can be a solution, a paste, a semi-solid, a dispersion, a suspension, a colloidal suspension or a mixture thereof. For inclusion of components that do not include NSAIDs, phospholipids themselves may participate in therapeutically beneficial effects to prevent and/or reduce ulceration in tissues, particularly ulcers caused by radiotherapy or chemotherapy.

Non-aqueous, flowable biocompatible carriers comprise a mixture of biocompatible oils or biocompatible oils or oily materials. The biocompatible oil or mixture of oils may naturally comprise a phospholipid or have a phospholipid incorporated therein. The amount of phospholipid present naturally or via the addition to the carrier is sufficient to prevent, reduce or treat ulceration of the tissue or, when the formulation comprises an NSAID (non-steroidal anti-inflammatory), is sufficient to reduce the pathogenic effects of the NSAID, such as gastrointestinal ulcers , bleeding, liver damage, kidney damage, and / or cardiovascular disease and / or side effects such as: high blood pressure, atherosclerosis, thrombosis, angina, stroke and myocardial infarction. The present inventors have also found that an aqueous emulsion of the composition shown above or a microemulsion-22-1353853 can be formed to treat oral, esophageal and gastrointestinal ulcers caused by radiation therapy and/or chemotherapy of various forms of cancer. Aqueous emulsions or microemulsions* • may be administered after radiation therapy and/or chemotherapy, before or during the period of radiation therapy and/or chemotherapy, and/or After taking it. In the prior publications and patents of the present inventors and others, compositions comprising phospholipids and NSAIDs are prepared by dissolving the shilling component in an organic solvent such as methyl sulphate, ethanol or chloroform, and then transferring the solvent by distillation or evaporation. Or formed; or the NS AID is dissolved in an aqueous solution with phospholipids added, followed by lyophilization to form. These methods allow the two components to chemically interact to form a complex. Among these methods, phospholipid choline (PC) is most often used as a phospholipid, which may be synthetically prepared such as dipalmitoside phosphocholine (DPPC) or in the form of a purified or semi-purified compound. The present invention is directed to pharmaceutical compositions or group φ compositions comprising a non-aqueous, flowable carrier comprising the phospholipid and any NS AID (non-steroidal anti-inflammatory agent), wherein the phospholipid is sufficient to prevent, reduce or treat tissue ulceration and / or an inflammatory amount is present, and when N SAID is present, the phospholipid is present in an amount that reduces the pathogenic effect of the NSAID. The blends are usually viscous solutions, pastes, semi-solids, dispersions, suspensions, colloidal suspensions or mixtures thereof and can be administered orally, directly, or internally or partially. The present invention is directed to pharmaceutical compositions or compositions comprising a non-aqueous, flowable carrier comprising the phospholipid and any NSAID (non-steroidal anti-inflammatory) wherein the phospholipid is sufficient to prevent, reduce or treat tissue ulcers and may be reduced The amount of NSAID gastrointestinal toxicity is present. Non-aqueous, fluid use -23- 1353853 The amount of NSAID with a high concentration of NSAID to reduce the effective medical amount. The blend is usually a viscous solution, paste, semi-solid, dispersion, suspension, colloidal suspension or a mixture thereof and can be administered orally, internally or partially.

The invention also encompasses a process for the preparation of a pharmaceutical composition or composition comprising the step of combining a solid NSAID (non-steroidal anti-inflammatory agent) with a non-aqueous carrier, wherein the carrier comprises a phospholipid-containing biocompatible oil or bio-available Compatible oils and phospholipids, or mixtures thereof, to form highly concentrated NSAID compositions having reduced pathogenic effects of NSAIDs.

The invention also encompasses methods of treating inflammatory, painful or other NSAID treatable conditions by administering an effective amount of a pharmaceutical comprising a non-aqueous, flowable carrier comprising NSAID (non-steroidal anti-inflammatory) and phospholipids. The composition is a mixture in which the phospholipid is present in an amount sufficient for the condition of the NSAID and the NSAID is present in an effective medical amount, wherein the combination of phospholipid-NSAID enables the amount of NSAID administered per dose to be lower than that of the phospholipid deficiency. The amount of NSAID required. The present invention also encompasses methods for preventing, reducing and/or treating ulcerated tissue and/or reducing inflammation, pain, or other NSAID treatable conditions associated with tissue inflammation and/or ulceration, by administering an effective amount A pharmaceutical composition comprising a phospholipid in a non-aqueous carrier and any NSAID, wherein the carrier is a biocompatible oil or a mixture thereof. In particular, the present inventors have discovered that a unique pharmaceutical composition comprising a biocompatible oil comprising a phospholipid such as a non-purified lecithin oil naturally comprising a phospholipid and wherein the resulting blend represents a solution, paste, semi-solid, dispersion -24- 1353853 Liquids, suspensions, colloidal suspensions or mixtures or compositions thereof have surprisingly low gastrointestinal toxicity and enhanced medical activity. · The composition is easily prepared by combining a biocompatible oil with phospholipids and any NSAID (non-steroidal anti-inflammatory), which is added directly to the crude or semi-crude lecithin oil in powder form. Forming pastes, semi-solids, dispersions or colloidal suspensions or similar compositions can be added to soft or hard gel capsules or vegicaps (made of plants) obtained from VitaHerb Nutraceutica 丨s of Placentia, φ CA Oral for injection, for internal administration or application to the skin for local administration. Surprisingly, as shown in Figures 1, 2 and 15, this simple blend is similar to the phospholipid choline-non-steroidal anti-inflammatory drug (PC-NS AID) product produced by the above conventional method, in NSAID-induced ulcers. Significantly low gastrointestinal toxicity in the rodent model of disease, as shown in Figures 3 and 4, with enhanced medical activity in the treatment of inflammation/pain in an acute model of paw inflammation, and as shown in Figures 7 and 8, in the spinal cord The chronic model of injury has enhanced medical activity to treat inflammation/pain φ. The weight ratio of NSAID (non-steroidal anti-inflammatory drug) to oil containing dish grease is typically in the range of from about 10:1 to about 1:10, preferably from about 4:1 to about 1:4, especially from about 2: 1 to about 1:2, especially from about 2:1 to about 1:1. In the case of natural oils containing phospholipids for use in the practice of the present invention, the oil typically contains from about 10 to about 15% by weight phospholipid, preferably from about 10% to about 20% by weight phospholipid, and especially from about 10% by weight to About 40% by weight of phospholipids. However, more or less phospholipids may also be used. However, at a weight of less than 10% by weight, it is necessary to be an effective medical amount or a sufficient amount to be [S] -25-1353853

The addition of the NSAID association, and above 40% by weight of the weight, necessitates the addition of the purified phospholipid to a biocompatible oil such as lecithin oil which naturally includes phospholipids. Phospholipids are added to the oil in the case of biocompatible oils containing low levels of phospholipids (less than about 1% by weight). This oil-phospholipid combination can be made to have a phospholipid concentration of up to about 90% by weight. However, the amount of phospholipids included in the desired combination is between about 10% and about 90% by weight, especially between about 20% and about 80% by weight, more particularly between about 20% and about 60% by weight, and It is especially between about 20% by weight and about 40% by weight.

In general, the compositions of the present invention containing NSAIDs (non-steroidal anti-inflammatory drugs) are generally used in a dosage range of 5 mg per dose or 500 mg per dose. Of course, smaller or higher dose blends may also be prepared; however, this dosage range covers the range of dosages commonly encountered with commercially available NSAIDS. The dosage of NSAID is preferably from about 10 mg to about 325 mg per dose, especially from about 25 mg to about 200 mg per dose, particularly from about 50 mg to about 100 mg per dose. It is to be understood that each NSAID has a different dosage range in each tablet and that these ranges encompass all ranges generally encountered by a patient ingesting a blend containing an NSAID as described herein. It must be understood that the compositions of the present invention include not only NSAIDs but also NSAIDs in non-aqueous, mobile carriers including phospholipids, wherein the amount of phospholipids is sufficient to enhance the efficacy of NSAIDs when NSAIDs are present, while reducing NSAIDs. Pathogenic effect. These NSAID pathogenic effects are of course specific for NSAIDs, but include, without limitation, gastrointestinal damage such as ulcers, bleeding, etc. (mostly NSAIDS), liver damage (eg, acetaminophen), kidney damage (eg, sedatives) Phenylpropionate -26- 1353853 \ (Ibuprofen), for Ethyronine, C0X-2 inhibitor), heart damage (eg, C0X-2 inhibitor), and the like. Because NSAID-phospholipid association is a mismatch, the dose of NSAID required to initiate a given therapeutic effect or response (lowering fever, reducing inflammation, lowering - platelet aggregation, etc.) is reduced. This reduction can range from a one-fold milligram dose to a 15-fold milligram dose reduction. It is best to reduce the milli-N SAID dose range from 1 to 10 fold. The increased biological activity provided by the phospholipid-NS AID-containing composition and φ does not equally increase the toxicity of the NSAID, but unexpectedly reduces the toxicity of the NS AID as demonstrated in the data presented herein. For more serious conditions such as arthritis, Alzheimer's disease, central nervous system and peripheral nervous system trauma, or other more serious conditions that can be treated with NS AID S (non-steroidal anti-inflammatory drugs) and/or phospholipids, NSAID The dose requirement per dose is usually much higher. Typical daily dosages range from about 1 mg to about 5000 mg per tweezers, preferably from about 500 mg to about 3000 mg per day, especially from about 750 mg to about 3000 mg per day, and especially Φ is about 1000 per day. From milligrams to about 3000 mg. Furthermore, the enhanced potency of the phospholipid-NSAID combination allows the dose to elicit greater efficacy without simultaneously increasing the pathogenicity and toxicity of the NSAID. Of course, the enhancement of the biological activity of this NSAID results in a reduction in the dose of N S AID administered. As a general practical method aspect, when an NSAID (non-steroidal anti-inflammatory drug) is administered as a compound of the present invention, wherein the NSAID is soluble, dispersed in 'suspended or otherwise mixed to a non-aqueous carrier, a biocompatible oil, Including a sufficient amount of phospholipids to enhance NSAID activity while reducing NSAID toxicity, the dose requirements may vary from patient to patient, condition and other factors to as low as 5% of the recommended dose required for the specific condition [S3 -27- 1353853 specific conditions] 100%. Preferably, the dosage is from about 10% to about 90% of the recommended dosage required to treat a particular condition and, in particular, from about 10% to about 50% of the desired dosage for the particular condition being treated. The recommended dose required for a given NSAID for a given condition can be found, for example, in the Physicians Desk Reference (PDR), the American Medical Association (ΑΜΑ) Gazette, and the US Food and Drug Administration (FDA) Gazette. And the specification has been fully established.

The composition of the present invention may also comprise: (1) a pharmaceutically acceptable amount of vitamin A, vitamin C, vitamin E or other antioxidants approved by the U.S. Food and Drug Administration (FDA) for human and animal consumption. The antioxidants and mixtures or combinations thereof selected; (2) pharmaceutically acceptable amounts of polyvalent cations selected from the group consisting of copper, zinc, gold, aluminum and calcium, and mixtures or combinations thereof; (3) pharmacy An acceptable amount of a formulation, a mixture or combination thereof, which is selected from the group consisting of dimethyl hydrazine/DMSO, propylene glycol/PPG, and medium chain triglyceride/MCT to improve flow, dispersibility or permeability; (4) a pharmaceutically acceptable amount of a food colored or non-toxic dye; (5) a pharmaceutically acceptable amount of a taste enhancer; (6) an excipient; and/or (7) an adjuvant. GENERAL COMPOSITIONS The present invention relates to a composition comprising a relatively high concentration of a non-steroidal anti-inflammatory drug (N SAID) in a non-aqueous, mobile carrier. The carrier preferably comprises a biocompatible oil and a phospholipid or a phospholipid-rich biocompatible oil. Natural and/or via added carriers include sufficient amounts of phospholipids to reduce the pathogenic effect of NSAIDs, increase the bioavailability of NSAIDs, and increase -28-1353853 plus NS AID across animal bodies including the relatively hydrophobic barrier of the human body Availability. Preferably, the resulting composition comprises a relatively high concentration of phospholipid-N SAID • associative complex. The resulting composition includes, inter alia, a relatively high concentration of phospholipid > choline-NSAID associative complex. The present invention relates to a composition comprising a relatively high concentration of NSAID in a non-aqueous, flowable carrier comprising a phospholipid and a biocompatible oil, wherein the phospholipid is sufficient to reduce the pathogenic effect of the NSAID, φ is increased The bioavailability of the NSAID, and the increase in the availability of the NSAID across the animal body, including the relatively hydrophobic barrier of the human body, wherein the dose of the composition is sufficient to deliver a therapeutically effective amount of NSAID and/or phospholipid, wherein the amount of NSAID is 1-10 times less than the amount of NSAID required to elicit the same effect in the absence of phospholipids. Preferably, the resulting composition comprises a relatively high concentration of phospholipid-NSAID associative complex. The resulting composition includes, inter alia, a relatively high concentration of phospholipid choline-NSAID associative complex. The presence of phospholipids in the compositions of the invention may also reduce the general φ and specific pathogenicity and/or toxicity of NS AIDS. Therefore, phospholipids can reduce and/or prevent liver damage caused by administration of acetaminophen and/or administration of other non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen or COX-2 inhibitors. Kidney and/or heart damage caused. GENERAL PROCESS FOR GENERAL COMPOSITIONS The present invention also relates to a process for preparing a composition comprising an NSAID in a non-aqueous, flowable carrier comprising combining an NSAID with a carrier to form a solution having a relatively high concentration of NSAID, a paste, a semi-solid , -29- 1353853 Steps of dispersion, suspension, colloidal suspension or mixtures thereof. Preferably, the carrier comprises a biocompatible oil or biocompatible oil and phospholipid containing phospholipids. Preferably, the resulting composition comprises a relatively high concentration of phospholipid-N SAID association complex. The resulting composition specifically includes a relatively high concentration of phospholipid choline-NSAID associative complex. Emulsified composition

The present invention also relates to an aqueous emulsion comprising a composition of a non-aqueous carrier, wherein the carrier comprises a biocompatible oil, a phospholipid sufficient to produce a medically beneficial effect, and a zero to effective medical amount of NSAID and when the NSAID is present, the amount of the phospholipid is also Sufficient to reduce the pathogenic effect of NS AID. The aqueous emulsion may also include a biocompatible emulsifier to maintain the composition in an emulsion state for a prolonged period of time. The carrier preferably comprises a biocompatible oil or biocompatible oil and phospholipid containing phospholipids. Preferably, the resulting emulsion comprises a composition having a relatively high concentration of phospholipid-NSAID associative complex. The resulting emulsions include, inter alia, compositions having relatively high concentrations of phospholipid choline-NSAID associative complexes. The invention also relates to an aqueous microemulsion comprising a composition of a non-aqueous carrier, wherein the carrier comprises a biocompatible oil, a phospholipid sufficient to produce a medically beneficial effect and a zero to effective medical amount of NSAID and the amount of phospholipid when the NSAID is present It is also sufficient to reduce the pathogenic effect of NSAID. The aqueous emulsion may also include a biocompatible emulsifier to maintain the composition in an emulsion state for a prolonged period of time. The aqueous microemulsion may also include a biocompatible emulsifier to maintain the composition in a microemulsion state for a prolonged period of time. The carrier preferably comprises a biocompatible oil or biocompatible oil and phospholipid containing phospholipids. Preferably, the resulting emulsion -30- 1353853 comprises a composition having a relatively high concentration of phospholipid-nsaid associative complex. The resulting emulsions include, inter alia, compositions having relatively high concentrations of phospholipid choline-NSAID association mismatches. The present invention also relates to a process for the preparation of an aqueous emulsion of the present invention which comprises adding a predetermined amount of the desired non-aqueous composition of the present invention to an aqueous solution in the absence or presence of an emulsifier, and then combining the composition with the solution. The step of mixing a period of time sufficient to form an emulsion, wherein the emulsifier, when present, is present in an amount sufficient to form a stable emulsion. The invention also relates to a process for the preparation of an aqueous microemulsion according to the invention, which comprises adding a predetermined amount of the desired non-aqueous composition of the invention to an aqueous solution in the absence or presence of an emulsifier, and then mixing the composition with the solution for a period of time sufficient to form an emulsion. The time is then followed by shearing the emulsion in a microemulsified condition to form a microemulsion wherein the emulsifier, when present, is present in an amount sufficient to form a stable φ microemulsion. The reason why the emulsifier is not necessary is because the pity itself has some emulsifying properties. Composition for treating inflammation The present invention also relates to a composition for reducing tissue inflammation, which comprises a non-aqueous carrier and the non-aqueous carrier comprises an effective medical amount of N SAID and a sufficient amount of phospholipids which reduce the pathogenic effect of NSAID, wherein the composition -31 - 1353853 at an NSAID dose that is generally lower than the dose required to initiate the same medical response under phospholipid deficiency can reduce tissue inflammation while reducing mucosal toxicity and/or irritation. Composition for the treatment of platelet aggregation

The invention also relates to a composition for reducing platelet aggregation, wherein the composition comprises a non-aqueous carrier and the non-aqueous carrier comprises an effective medical amount of NSAID and a sufficient amount of phospholipids which reduce the pathogenic effect of NSAID, wherein the composition is lower than the phospholipid The lack of an NSAID dose that normally triggers the same medical response reduces platelet aggregation and reduces mucosal toxicity and/or irritation. Composition for treating fever

The invention also relates to a composition having anti-pyrogenic activity, wherein the composition comprises a non-aqueous carrier and the non-aqueous carrier comprises an effective medical amount of NSAID and a sufficient amount of phospholipids which reduce the pathogenic effect of NSAID, wherein the composition is lower than the phospholipid The lack of NSAID dose at the dose required to trigger the same medical response has anti-pyrogenic activity while reducing mucosal toxicity and/or irritation. Composition for treating ulcer and/or inflamed tissue The present invention also relates to a composition for treating ulcerated tissue, wherein the composition comprises an aqueous emulsion or microemulsion comprising a phospholipid, a biocompatible oil and a zero to effective medical amount NSAID, Wherein the phospholipid is present in an amount sufficient to reduce tissue inflammation and/or ulceration and the NSAID, when present, reduces inflammation of the affected area of the tissue. -32- 1353853 Composition for the treatment of oral ulcers and/or inflammation - The present invention also relates to mouthwashes comprising an aqueous emulsion or micromolecule containing phospholipids, biocompatible oils and zero to effective medical amount NS AID An emulsion wherein the phospholipid is present in an amount sufficient to reduce mouth ulcers and/or inflammation and the NSAID, when present, reduces inflammation in the affected area of the mouth. #'therapy mouth, composition of esophagus and gastrointestinal tract ulcers The present invention also relates to a pharmaceutically acceptable pharmaceutical agent comprising an aqueous emulsion or microemulsion comprising a phospholipid, a biocompatible oil and a zero to effective medical amount NSAID, Wherein the phospholipid is present in an amount sufficient to reduce inflammation and/or ulceration of the mouth, esophagus and/or gastrointestinal tract and the N SAID, when present, reduces inflammation of the oral 'esophageal and/or affected areas of the gastrointestinal tract. Composition for treating inflammation of the eye

The invention also relates to eye drops comprising an aqueous emulsion or microemulsion comprising a phospholipid biocompatible oil in an aqueous solution and a zero to effective medical amount N SAID, wherein the phospholipid is sufficient to reduce inflammation or irritation of the eye The amount present and the NS AID, when present, can reduce ocular inflammation associated with uveitis or related eye conditions. Method of Treating Ulcers and/or Inflamed Tissues The present invention also relates to the treatment of oral, esophagus, gastrointestinal tract, ocular and/or other inflammatory and/or ulcerated tissues by administering the emulsions or microemulsions of the present invention [-33- 1353853 A method of inflammatory and/or ulcerative conditions. Composition for the treatment of central and/or peripheral nervous system praying

The invention also relates to a composition for the treatment of spinal cord, stroke and/or traumatic brain injury by oral or internal treatment, wherein the composition comprises a non-aqueous carrier containing phospholipids and a effective medical amount of NSAID or comprises an existing phospholipid and an effective medical amount NSAID An aqueous solution (eg, an emulsion or microemulsion) in which the non-aqueous carrier is dispersed, wherein the phospholipid can increase NS AID delivery to cross the blood-brain barrier to allow more NSAIDs to reach the site of the trauma and reduce inflammation, wherein the NSAID can reduce inflammation , platelet aggregation, anti-pyrogenic activity and cell death due to inflammation. Method for treating central and/or peripheral nervous system trauma

The invention also relates to the treatment of spinal cord, stroke and/or trauma by injection into a vein (intravenous administration), in an artery (intra-arterial administration) or directly into a traumatic position (direct administration). A method of brain injury, in which, when administered intravenously or intraarterially, phospholipids can increase NSAID delivery to cross blood-brain barriers or other neurogenic barriers to allow more NSAIDs to reach the site of trauma and reduce inflammation and phospholipids at all The effect of NSAID can be reduced in the form of administration. The invention also relates to an agent for ameliorating the symptoms of spinal cord injury, stroke and/or traumatic brain injury, wherein the medicament comprises a relatively high concentration of NSAID in an oil-based or water-based carrier containing phospholipids, wherein the NSAID and the phospholipid In the form of an associative complex formed in the medicament, the composition of -34-1353853 comprises a sufficient concentration of NSAID to reduce the swelling of the traumatic tissue and a sufficient concentration of phospholipids to reduce the pathogenic effect of the NSAID on the injured tissue. Composition for treating Alzheimer's disease The present invention also relates to a composition for preventing, treating or ameliorating symptoms associated with Alzheimer's disease, the composition comprising a biocompatible oil, phospholipid φ and effective The medical amount NSAID, in which NSAID and phospholipid are used to prevent the onset of symptoms of Alzheimer's disease or to improve the symptoms of Alzheimer's disease. Method for treating Alzheimer's disease The present invention also relates to a method for preventing, treating or ameliorating symptoms associated with Alzheimer's disease, which comprises administering the composition of the present invention orally and/or internally according to a treatment plan The steps to commit. φ Composition for treating an incision The present invention also relates to a composition for treating an incision to reduce surgically induced local inflammation and accelerate healing, the composition comprising a biocompatible oil, a phospholipid and an effective medical amount NSAID, wherein the NSAID and the phospholipid It is used to reduce inflammation and related symptoms and accelerate healing. Method for treating an incision The present invention also relates to a method for treating an incision to reduce surgically-induced local inflammation and accelerate healing, comprising a composition comprising a biocompatible oil, phospholipid-35-1353853 and an effective medical amount NS AID During and after surgery, but before sealing, it is applied to the surgical site where N SAID and phospholipids are used to reduce inflammation and related symptoms and accelerate healing. Desirable therapeutic compositions of the invention include emulsions or microemulsions in spray application form or similar compositions of the compositions of the invention. Composition for improving ulceration and/or inflammation caused by radiation therapy and/or chemotherapy The present invention also relates to amelioration of tissue ulcers such as mucositis or related conditions induced by radiation therapy and/or chemotherapy of certain cancers. The composition, wherein the composition comprises a biocompatible oil, a phospholipid and any effective medical amount of NSAID, wherein the phospholipid is present in an amount sufficient to prevent and/or reduce ulceration or inflammation associated with mucositis and when an NSAID is present Phospholipids are present in an amount that not only prevents and/or reduces ulceration or inflammation, but also ensures that the NSAID does not further aggravate the condition. For chemotherapeutics, the chemotherapeutic agent is preferably administered with a suitably formulated composition of the invention. Therefore, if the chemotherapeutic agent is administered orally, the chemotherapeutic agent can be mixed with the appropriately formulated composition of the present invention, but the chemotherapeutic agent must not be adversely interacted with the components of the composition of the present invention and then administered to the disease. Suffering. If an adverse interaction occurs between the chemotherapeutic agent and the components of the composition of the invention or if the chemotherapeutic agent is administered by injection, the composition of the invention is administered orally after administration of the chemotherapeutic agent for a sufficient period of time. To prevent or reduce the time of mucositis. -36- 1353853 Method for improving ulceration and/or inflammation caused by radiation therapy and/or chemotherapy' • The present invention also relates to prevention and/or treatment for medical treatment such as radiation, therapy and/or chemistry A method of treating mucositis or other ulcer conditions induced by therapy, the method comprising administering an effective amount of a composition of the invention comprising a biocompatible oil, a phospholipid, and any effective medical amount NS AID, wherein the phospholipid is sufficient to prevent And/or reduce the amount of ulcers or inflammation associated with mucositis. In addition, when NSAID is present, phospholipids not only prevent and/or reduce ulcers, but also ensure that NS AID does not further aggravate the condition. The amount is present, prior to and/or after the radiation therapy and/or chemotherapy, to the step of the affected area of the body. Preferably, the composition is designed for oral administration and is administered prior to and concurrent with radiation therapy and/or chemotherapy to prevent and/or treat and/or reduce the time of mucositis. In the case of oral administration of the composition of the present invention, it is preferred to disperse the components in the form of droplets in an aqueous solution to form an emulsion, a microemulsion or the like. Droplets Φ may include emulsifiers, suspending agents, and other ingredients commonly found in mouthwashes. The compositions of the present invention can be used in combination with any of the mouthwashes or oral health care compositions including those described in U.S. Patent Nos. 5,407,663, 5,236,699, 5,130,146, 5, 085, 850, incorporated herein by reference. . The composition of the present invention may also be administered as a paste, a lozenge, or other type which is commonly used for oral administration. Of course, the composition can also be included in capsules, gel capsules. For topical administration, the compositions of the present invention may be in the form of an ointment, paste, oil, emulsion, microemulsion, or a mixture or combination thereof. Moreover, the composition can be combined with other ingredients commonly used in the ointment and cosmetic industries. [S 1 -37- 1353853 emulsion

The compositions of the present invention can be prepared and formulated in the form of an emulsion. The emulsion is usually a liquid usually in excess of hydrazine. A droplet of 1 micron diameter is in the form of a multiphase system dispersed in another liquid. (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1 98 8, Marcel Dekker, Inc., New York, NY, volume 1, p_ 199; Rosoff, in Pharmaceutical DOSAGE forms, Liebrman, Rieger and Banker (Eds.), 1 98 8, Marcel Dekker, Inc., New York, NY ? Volume 1, p. 245; Block in Pharmaceutical

Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1 988, Marcel Dekker, Inc., New York, N. Y. 5 volume 2, p. 33 5;

Higuchi et al, in Recington's Pharmaceutical Sciencs, Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are typically two-phase systems consisting of two insoluble liquid phases that are intimately mixed and dispersed with one another. Typically, the emulsion can be in the form of a water-in-oil (w/o) or oil-in-water (o/w). When the aqueous phase is subdivided into and dispersed as fine droplets into a large amount of the oil phase, the resulting composition is referred to as a water-in-oil (W/O) emulsion. On the other hand, when the oil phase is subdivided and dispersed in the form of fine droplets into a large amount of the aqueous phase, the resulting composition is referred to as an oil-in-water (0/W) emulsion. The emulsion may contain other components in addition to the dispersed phase and the effective drug may be dissolved in the aqueous phase, in the form of a solution in the oily phase or may itself be in the form of a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and antioxidants can also be present in the emulsion as desired. The pharmaceutical emulsion may also be a multilayer emulsion composed of two or more phases of -38 to 1353853 1 such as a water-in-oil oil (ο/w/o) and a water-in-oil-in-water (W/0/W) emulsion. This complexed blend typically provides a dual phase emulsion. • No advantages. In a multi-layer emulsion, individual oil droplets in the 0/W emulsion are enclosed. - The water droplets constitute a water-in-oil-in-water (w/〇/w) emulsion. Similarly, a system in which oil droplets stabilized in the oil phase enclose the oil droplets provides a water-in-oil (o/w/o) emulsion. Emulsions are characterized by little or no thermal stability. Generally, the emulsion component Φ the dispersed or discontinuous phase is sufficiently dispersed in the external or continuous phase and remains in this form via the viscosity of the vehicle or blend of the emulsifier. Either phase of the emulsion can be semi-solid or solid, such as emulsion-type ointment bases and emulsifiable concentrates. Other methods of stabilizing the emulsion require the use of an emulsifier which can be placed in either phase of the emulsion. Emulsifiers can be divided into four categories: synthetic surfactants, naturally occurring emulsifiers, absorbent bases, and finely divided solids. (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.) 5 1 9 8 8 , Marcel Dekker, Inc., New York, N. Y. 5 vo lume 1, p. 1 99). Synthetic surfactants have been found to be widely used in emulsion blends and can be reviewed in the literature. (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1 988, Marcel Dekker, Inc., New York, NY5 volume 1, p.285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc. 5 New York, NY3 1 9 8 8, volume l, p. 199). Surfactants are generally amphiphilic and comprise hydrophilic and hydrophobic moieties. The ratio of the hydrophilicity to the hydrophobicity of the surfactant -39 - 1353853 is called hydrophilic/lipophilic balance (HLB) and is a useful tool for classifying and selecting surfactants in the preparation of blends. Surfactants can be classified into different classes depending on the nature of the hydrophilic group: nonionic, anionic, cationic and zwitterionic (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1 988,

Marcel Dekker, Inc., New York, N. Y., volume l, p. 2 8 5).

Naturally occurring emulsifiers used in emulsion blends include lanolin, beeswax, phospholipids, lecithin and acacia. The absorbent bases are hydrophilic in nature so that they absorb water to form a water-in-oil (w/o) emulsion and still retain their semi-solid consistency such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have been used as good emulsifiers, especially in combination with surfactants and in viscous formulations. These include polar inorganic solids such as heavy metal hydroxides, intumescent clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum citrate and colloidal aluminum magnesium citrate, etc. And non-polar solids such as carbon or glyceryl tristearate.

A wide variety of non-emulsifying materials are also included in the emulsion blend and contribute to the properties of the emulsion. These include fats, oils, waxes, fatty acids, humectants, hydrophilic colloids, preservatives and antioxidants (Block in Pharmaceutical

Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1 988, Marcel Dekker, Inc., New York, NY, volume l, p.3 3 5; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds .), 1 9 88, Marcel Dekker, Inc., New Y ork, N. Y ·, vo 1 ume 1, p. 1 9 9). Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymeric-40-1353853 (eg, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), fibers Derivatives (for example, carboxymethylcellulose and carboxypropylcellulose), and synthetic polymeric oximes (such as polymeric gum carbomers, cellulose ethers, and carboxyvinyl polymers). They are dispersed or expanded in water to form a colloidal solution which stabilizes the emulsion by forming a strong interfacial film around the dispersed phase droplets and by increasing the viscosity of the external phase.

Since emulsions usually contain ingredients that readily support the growth of microorganisms such as sugars, proteins, sterols and phospholipids, preservatives are often placed in these blends. Preservatives commonly used in emulsion blends include methylparaben, propyl paraben, quaternary ammonium, benzalkonium chloride, esters of para-hydroxybenzoic acid, and boric acid. Antioxidants are also often added to emulsion formulations to prevent deterioration of the blend. The oxidizing agent used may be a radical scavenger such as tocopherol, alkyl decanoate, butylated hydroxyanisole, butylated hydroxytoluene, or a reducing agent such as ascorbic acid and sodium metabisulfite, and the like, and an antioxidant synergist such as Citric acid, tartaric acid, and lecithin. The use of emulsion blends via the skin, oral and parenteral routes, and their methods of manufacture have been reviewed in the literature. (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1 98 8.

Marcel Dekker, Inc., New York, N. Y., volume l, p. 199). Emulsion compositions for oral delivery are extremely widely used because of their ease of formulation, absorption and bioavailability. (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and t S 1 -41 - 1353853

Banker (Eds.), 1 988, Marcel Dekker, Inc., New York, N. Y., volume, p. 24 5 ; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Ma Reel

Dekker, Inc., New York, N. Y., volume 1, ρ.199) β mineral oil based laxatives, oil-soluble vitamins and high-fat nutrient preparations are commonly used in the form of oil-in-water (〇/w) emulsions. Among the materials that are taken orally.

Microemulsions In one embodiment of the invention, the compositions of the invention are formulated as microemulsions. Microemulsions can be defined as systems of water, oil and amphiphiles, which are single optical isotropic and thermostatic liquid solutions (Rosoff, in

Pharmaceutical Dosaage Forms, Lieberman, Riger and Banker (Eds.), 1 98 8, Marcel Dekker, Inc., New York, N. Y., volume l, p. 245). Microemulsions are typically prepared by dispersing the oil in a solution of an aqueous surfactant and then adding a sufficient amount of a fourth component, typically a medium chain length, to form a transparent system. Therefore, the microemulsion is also referred to as the thermal stability consisting of two immiscible liquids stabilized by the interface film of surface-activated molecules, and is a clear dispersion (Leung and Shah, in: Controlled Release of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed., 1 989, VCH Publishers, New York, pages 185-215). Microemulsions are typically prepared by a combination of three to four components including oil, water, surfactants, coactivators, and electrolytes. Whether the microemulsion is water-in-oil (W/0) or oil-in-water (0/W) type depending on the nature of the oil and surfactant used -42- 1353853 and the polar head and hydrocarbon end of the surfactant molecule Structural and geometrical arrangements (Schott, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 189, p. 271). Phenomena methods using phase diagrams have been extensively studied and well-known to those skilled in the art have gained a wide range of knowledge on how to formulate microemulsions. (Rosoff, in Pharmaceutical Dosage Forms, Li eberman, Rieger and

Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N. Y., volume 1, p. 24 5 ; Block, in Pharmaceutical Dosage Forms, Liebrman, Rieger and Banker (Eds.), 1 988, Marcel Dekker, Inc., New York, NY, volume 1, p. 335). Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, nonionic surfactants, Brij 96, polyethylene oxide oleyl ether, polyglycerin fatty acid esters, tetraglycerol monolaurate (ML3 10), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO50 0), decaglycerin monodecanoate (MCA 750), decaglycerin Oleic acid ester (MO750), decaglycerin sesquioleate (SO 75 0), decaglycerin decaoleate (DAO 75 0), used alone or in combination with a co-surface activator. Co-surfactants, usually short-chain alcohols such as ethanol, 1-propanol, and 1-butanol, are infiltrated into the surfactant film and thus due to void spaces created in the surfactant molecules A disordered film is used to increase the fluidity of the interface. However, microemulsions can be prepared without the use of co-surfactants, and alcohol-free self-emulsifiable microemulsions are known in the art. The aqueous phase can be generally, but not limited to, water, aqueous solutions of the drug, glycerin, polyethylene glycol 300, polyethylene glycol 400, polyglycerols, C [-43-1353853 glycols, and ethylene glycol. a derivative. The oil phase may include, but is not limited to, materials such as Captex 300, Captex 355 > Capmul MCM, hydroxy fatty acid ester, medium chain (C 8-Cl 2) mono-, di-, and tri-glyceride, poly Oxygenated ethylated fatty acid glycerides, fatty alcohols, PEGylated glycerides, saturated PEGylated C8-C10 glycerides, vegetable oils and oxime oils.

Microemulsions are particularly interesting because they are based on the dissolution of drugs and enhance the absorption of drugs. Fat-based microemulsions (oil-in-water (〇/w) and water-in-oil (w/o)) have been proposed to enhance the oral bioavailability of drugs, including peptides (Constantinides et al., Pharmaceutical Research, 1 994,11,1 3 85 - 1 3 90; Ritschel, Meth Find. Exp. Clin· Pharmacol, 1 993, 13, 205). The micro-emulsion can improve the dissolution of the drug, avoid the hydrolysis of the drug enzyme, and may enhance the absorption of the drug due to the change of the membrane fluidity and permeability induced by the surfactant, and it is easy to be orally administered than the solid dosage form, improve the clinical efficacy, and reduce The advantage of toxicity. (Constantinides et al., Pharmaceutical Research, 1994, 11, 1 3 85; Ho et al., J. Pharm. Sci., 1 995, 85, 1 3 8- 1 43). Miniemulsions can naturally form when their components are combined together at room temperature. Microemulsions are also effective in transdermal delivery of active ingredients in cosmetic and pharmaceutical applications. The microemulsion compositions and compositions of the present invention are expected to be administered orally and via the intestinal tract to increase the medical response by phospholipids and/or non-steroidal anti-inflammatory drugs (NS A ID)-phospholipid combinations, as well as to improve phospholipids and/or Or a non-steroidal anti-inflammatory drug (NSAID)-phospholipid combination of local cellular medical responses and absorption through a hydrophobic barrier such as the gastrointestinal tract, central nervous system, peripheral nervous system - 44 - 1353853 * system, vagina, mouth, esophagus, cheek Barriers in the cavity, nasal cavity, treasure cavity and other areas of the permissive area. - The microemulsion of the present invention also contains other components and additives such as mountain > • sorbitan monostearate (Grill 3), Labrasol, penetration enhancer, etc. to improve the properties of the blend and The absorption of the phospholipid and/or non-steroidal anti-inflammatory (NS AID)-phospholipid combination containing the blend of the invention is enhanced. The penetration enhancer used in the microemulsion of the present invention can be classified into one of five broad categories of surfactants - surfactants, fatty acids, bile salts, chelating agents, and non-covalent non-surfactants (Lee). Et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of these categories has been discussed above. Suitable phospholipids for use in the present invention include, but are not limited to, dimyristoyl phosphatidylcholine, distearyl phospholipid choline, diterpenoid phospholipid choline (DLL-PC) > Phospholipid choline (DPPC), soybean phospholipid choline (Soy-PC or PCS) and lecithin choline (Egg-PC or PCE). In dipalm Φ 醯-phospholipid choline (DPPC), saturated phospholipids, saturated aliphatic substituents I and R2 are CH3--(CH2)14, R3 is CH3, and X is H. In diterpenoid-phosphocholine (DLL-PC), unsaturated phospholipids, Ri and R2 are CH3--(CH2)4--CH=CH--CH2-·C Η = = C Η - - ( C Η 2) 7, R3 is CH3 ' and X is Η. In the mixture of lecithin choline (Egg-PC), an unsaturated phospholipid, 'Rl mainly contains a saturated aliphatic substituent (such as palm or stearic acid)' and R2 is mainly an unsaturated aliphatic substituent (such as oleic acid or Arachidonic acid). In soybean phospholipid choline (Soy-PC), in addition to saturated phospholipids (palmitic acid and stearic acid), it is also a mixture of unsaturated phospholipids [oleic acid, linoleic C S3 -45-1353853 acid and linolenic acid] . Desirable zwitterionic phospholipids include, but are not limited to, dipalmitoside-phospholipid choline, phosphocholine, or mixtures thereof. Suitable non-steroidal anti-inflammatory drugs (NS A ID) include, but are not limited to, propionic acid drugs such as phenoxy hydrogenated atropine #§(Fe no pro fen ca 1 cium) (N a 1 f ο η. RT Μ .) > Flurbiprofen

(Ansaid .RTM.), Suprofen, Benoxaprofen > I buprofen (prescription Motrin .RTM ·), Ibuprofen ( Ibuprofen) (200 mg. Over-the-counter Nuprin, Motrin IB.RTM.), Ketoprofen (Orduis, Oruvall. RTM_), Naproxen (Naprosyn.RTM.), methoxynaphthalene Sodium propionate (Aleve, Anaprox, Aflaxen.RTM·), D. oxaprozin (Daypro.RTM·), etc.; Acetic acid drugs such as Diclofenac sodium (Voltaren.RTM.) 5 D i cl ofenac potassium (Cataflam .RTM.), Etodolac (Lodine .RTM.) > Indomethacin (Indocin.RTM.), ketopro Ketorolac tromethamine (Acular, Toradol.RTM. intramuscular), Ketorolac (oral Toralol.RTM.), etc.; ketones such as Nabumetone (Relafen. RTM. ), Su 1 indac ( C1 i η 〇 ri 1 . RT Μ.) ' 妥 ο 1 metins 〇dium (Tolectin .RTM.) 'etc. Fenamate drugs such as Meclofenamate sodium (Meclomen.RTM.) » Mefenamic acid (Ponstel.RTM·), etc.; oxicam (〇xicam) drugs such as Piroxicam (Dolibid.RTM.), et al; salicylic acid-46- 1353853 such as Diflunisal (Feldene.RTM·), aspirin, etc; pyrazole Oleic acid drugs such as Oxyphenbutazone (Tandearil.RTM.), phenylbutazone ( _

Phenylbutazone) (Butazolidin.RTM.), et al; acetaminophen (Tylenol.RTM.), etc.; C0X-2 inhibitors such as Celebrex, Vioxx, etc. , or a mixture or combination thereof.

Suitable biocompatible emulsifiers include, but are not limited to, ionic or nonionic emulsifiers or surfactants which are recognized for human or animal consumption or for internal use. Examples include acetylated monoglycerides, aluminum salts of fatty acids, arabinogalactan, Becker's yeast polysaccharides, calcium carbonate, calcium salts of fatty acids, locust bean gum, guaran gum, edible fat or Oil mono- and diglyceride or edible fat-forming fatty acid di-tartrate, sodium dioctyl thiosuccinate, disodium phosphate (X-ref-sodium phosphate, mono-, di-, and ·), ethoxylated mono- and di-glycerides, Eucheuma cottonii extract, Eucheuma spinosum extract, fatty acids, (aluminum, calcium, magnesium, potassium and sodium) salts, Food starch esterified with n-octenyl succinic anhydride which has been treated with /3-amylase, furcellan (Furcelleran), furcellan (Furcelleran), quercetin, ammonium, calcium, potassium, or sodium Salt, Indian gum, cedar extract, glycerol-lactate of fatty acids, oleic acid hexitol, hydroxylated lecithin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, glycerol and propylene glycol Acid ester, fatty acid lactate, lecithin, hydroxylated lecithin, methyl ethyl cellulose , edible fat or oil, or edible fat-forming acid, -47- 1353853

Mono- and diglycerides, monoisopropyl citrate, edible fats or oils, or edible fatty acid-forming acids, mono- and diglycerides monosodium phosphate derivatives, Myrj 45 (polyethylene oxide) 8-stearate), bovine bile extract, pectin (including modified pectin), polyethylene glycol (400) dioleate, polyglycerol fatty acid ester, polyoxyethylene glycol (400) single-and Di-oleate, Tween 60 (polyoxyethylene (20) sorbitan monostearate), Tween 65 (polyoxyethylene (20) sorbitan tristearate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), potassium salt of fatty acids, propylene glycol alginate (propylene glycol alginate), propylene glycol mono- and di-ester of fats and fatty acids, rapeseed oil , fully hydrogenated, hyperglycerolated, sodium acid pyrophosphate, sodium aluminum phosphate, sodium hypophosphite, sodium lauryl sulfate, sodium metaphosphate, sodium methyl sulfate, sodium pectate, sodium salt of fatty acid, sodium stearyl lactate , thio-sodium acetate derivatives (mono- and di-glycerides), sorbitan monooleate, sorbitan monostearate Ester, amber deuterated monoglyceride, succinic acid stearyl propylene glycol, sucrose isobutyrate (SAIB), sucrose fatty acid ester, sulphated butyl oleate, trisodium phosphate, xanthan gum, etc. a mixture or combination thereof. Suitable neutral fats include, but are not limited to, any neutral fat such as triglyceride. A list of representative neutral fats, such as triglycerides, is particularly specific to U.S. patents. Mentioned in 4,950,656 and 5,043,329. Both saturated and unsaturated triglycerides can be used in the present composition, and include, for example, glyceryl tripalmitate, vinegar, triolein, linolenate, and (unsaturated). However, these particular triglycerides are here for convenience only and are representative of only a variety of useful triglycerides. -48- 1353853 Suitable biocompatible, non-limiting examples of biodegradable polymers include polylactate, polyglycolate, polycaprolactone, polyanhydride, poly-amine, polyamine Ethyl carbamate, polystearylamine, polyorthoester, polydioxane, alkanone, polyacetal 'polyketal, polycarbonate, polyorthocarbonate, polyphosphazene' polyhydroxybutyrate 'Polyhydroxyvalerate, polyoxalate, polyalkylene succinate, poly(malic acid), poly(amino acid), poly(methyl vinyl ether), poly(maleic anhydride) Butadiene, deacetylated chitin, and copolymerized φ ' terpolymer, or its higher poly-monomer polymer or combinations or mixtures thereof. The ideal biodegradable polymer can be completely degraded by hydrolysis. The polymer is typically a surface corrosive polymer such as a polyanhydride or an overall corrosive polymer such as a polyorthoester. Poly(1-lactic acid) (P1LA), poly(dl-lactic acid) (PLA), poly(glycolic acid) (PGA), polycaprolactone, copolymer, terpolymer, high-grade poly-monomer , or a combination or mixture thereof, is an ideal biocompatible, biodegradable polymer. The biodegradable copolymer of claim 9 is a copolymer of lactic acid and glycolic acid, sometimes referred to as poly(dl-lactic-co-glycolic acid) (PLG). The ratio of the co-monomer (lactic acid ester: hydroxyacetate) of poly(DL-lactic acid-co-glycolic acid) is preferably about 1 〇〇: 〇 to about 50:50 lactic acid to hydroxyacetic acid ratio . The ratio of lactic acid to glycolic acid is preferably between about 8 5 : 15 and about 5 0 : 50. a blend of poly(dl-lactic acid) (PLA) and poly(dl-lactic acid-co-glycolic acid) (PLG), preferably from about 85:15 to about 50:50 PLA to PLG ratio, also used to prepare ' Polymer material. Poly(cU-lactic acid) (PLA), poly(1-lactic acid) (P1LA), poly(hydroxyethyl-49-1353853 acid) (PGA), poly(dl-lactic acid-co-glycolic acid) (PLG) and Combine or mix

The compound or blend is in a synthetic polymer that is approved for clinical use in humans. They are now used as surgical suture materials and in controlled release devices as well as in other medical and pharmaceutical applications. They are biocompatible and their degradation products are low molecular weight compounds such as lactic acid and glycolic acid that can be incorporated into the metabolic pathway. Further, the poly(lactic acid-co-glycolic acid) copolymer can provide a wide range of degradation rates from several days to several years as long as the copolymer ratio of lactic acid to glycolic acid is changed.

To enhance the biodegradation of the polymer used in biological applications, enzymes which contribute to the biodegradation of the polymer used in the composition may also be added to the compositions of the present invention. An ideal enzyme or similar reagent is a protease or a hydrolase having an ester-hydrolyzing ability. Such enzymes include, but are not limited to, proteinase K, pineapple enzyme, pronase E, cellulase, glucanase, elastase, plasmin, streptokinase, trypsin, chymotrypsin, papaya Protease, papain, collagenase, subtilisin, fusopeptide A, fig protease, carboxypeptidase A, pectinase, pectin esterase, oxidoreductase, oxidase, and the like. A suitable amount of this degradation enhancer can be used to adjust the durability of the implant. Suitable chemical and/or radiotherapeutic agents (trade names) include, but are not limited to, complex platinum, complex gold (ΠΙ), complex palladium, alitretinoin (Panretin), and allopurinol ( Zyloprim), altretamine (Hexalen), amifostine (Ethyol), amifostine (Ethyol), amifostine (Ethyol), anastrozole (Arimidex), -50- 1353853

Anastrozole (Arimidex), arsenic trioxide (Trisenox) 'bexarotene (Targretin) 'bexarotene (Targretin), bleomycin (Blenoxane), mesamine ( Busulfan intravenously (Busulfex), mesalamine (busulfan oral) (Myleran), capecitabine (Xeloda) 'capecitabine (Xeloda), capecitabine (Xeloda), card Carboplatin (Paraplatin), carboplatin (Paraplatin), dichloroethyl nitrosourea (carmustine) and Polifeprosan 20 implant (Gliadel Wafer) » ce 1 ecoxib (Celebrex) , chlorambucil (Leukeran), cisplatin (Platinol), cisplatin (Platinol), cisplatin (Platinol), 2-chlorodeoxyadenosine ( Cladribine) (Leustatin 2-CdA), cyclophosphamide (Cytoxan), cytarabine liposome (DepoCyt), daumycin Xolipids (DaunoXome) > Daunorubicin, Cerubidine, dexrazox Ane) (Zinecard), docetaxel (Taxotere), docetaxel (Taxotere), docetaxel (Taxotere), doxorubicin (Adriamycin PFS injection), doxorubicin microlipid (Doxil) ), doxil, Elliott's solution, epirubicin (Ellence), estramustine (Emcyt) 'etoposide phosphate (Etopophos) 'et〇p〇side phosphate (Etopophos) 'et〇p〇side phosphate 1353853

(Etopophos), et〇p〇side (VP-16 (Vepesid), etoposide (VP-16 (Vepesid), exemestane (Aromasin), Fluorine Fludarabine (Fludara), fluorouracil (5-FU (Adrucil), gemcitabine (Gernzar), gemcitabine (Gemzar), gemtuzumab-ozogamicin (M y 1 ot Ar g), g 〇sere 1 in acetate (Zoledex implant), hydroxyurea (Hydrea capsule), idarubicin (Idamycin), idarubicin (Idamycin), different Cyclophosphamide (if0Sfamide) (IFEX), imatinib mesylate (Gleevec), irinotecan (Camptosar), irinotecan (Camptosar) , irinotecan (Camptosar), letrozole (Femara), letrozole (Femara), leucovorin (Leucovorin), levamisole (levamisole) (Ergamisol) L-lysostatin (me 1 pha 1 an L-PAM)

(Alkeran), mesna (Mexnex), Methotexate, methoxsalen (Uvadex), mitoxantrone (Novantrone), mitoxantrone (Novantrone) ), paclitaxel (Paxene), paclitaxel (Taxol), paclitaxel (Taxol), paclitaxel (Taxol), paclitaxel (Taxol), paclitaxel ( Paclitaxel) (Taxol), paclitaxel (Taxol), paclitaxel (Taxol), paclitaxel -52- 1353853

(Taxol), pamidronate (Aredia), Pegademase (Adagen (Pegademase Bovine), pentostatin (Nipent), pentostatin (Nipent) ), porfimer sodium (Photofrin) 'porfimer sodium (Photofrin), porfimer sodium (Photofrin), streptozocin (Zanosar), Talcrosol, tamoxifen (Nolvadex), tamoxifen (Nolvadex), tamoxifen (Nolvadex), tamoxifen (Nolvadex), tamoxifen (Nolvadex), tamoxifen ( Tamoxifen) (Nolvadex), tamoxifen (Nolvadex), tamoxifen (Nolvadex), temozolamide (Temodar), teniposide VM-2 6 (Vumon), topologically Top otecan (Hycamtin), topotecan (Hycamtin), toremifene (Fareston), tretinoin ATRA (Vesanoid), valrubicin (V al star) ) , vinorelbine (Navelbine), or a mixture or combination thereof. Of course, radiation therapy may also include conventional radiation therapy. Although the invention is preferably directed to the use of unpurified lecithin oil, the invention may also be used Any biocompatible oil containing phospholipids, including, but not limited to, any human consumable oil containing phospholipids. Biocompatible oils include, but are not limited to, by the Food and Drug Administration (FDA) Any oil approved for human or animal consumption, including natural [-53- 1353853 oils such as vegetable or animal oils or their derivatives or synthetic oils and especially natural oils rich in phospholipids such as lecithin oil from soybeans. Examples of the class include essential oils, vegetable oils, hydrogenated vegetable oils, animal oils such as peanut oil, mustard oil, avocado oil, safflower oil, olive oil, corn oil, soybean oil, sesame oil, vitamin A, vitamin D, vitamin E, fish oil and the like.

The compositions or compositions of the present invention may also include other chemicals such as antioxidants (e.g., vitamins A, C, D, E, etc.), trace metals and/or multivalent cations (aluminum, gold, copper, zinc, calcium, etc.) ), surfactants and / or solvents (such as propylene glycol / PPG, dimethyl nitrite / DMSO, medium chain triglyceride / MCT, etc.), non-toxic dyes and flavoring agents can be added to the blend to improve stability , liquidity / dispersion, permeability, effectiveness and consumer acceptance.

Blends comprising phospholipids, preferably phospholipids (PC) and non-steroidal anti-inflammatory drugs (NSAIDs), can be used for oral administration to soft gel capsules or hard gels or vegicaps (shells made of plants). Alternatively, it may be topically applied to the inflamed, ulcerated and/or irritated tissue or skin in the form of a solution, paste, semi-solid, dispersion, suspension, colloidal suspension or mixtures thereof. One desirable embodiment of the present invention is a phospholipid choline-non-steroidal anti-inflammatory drug (PC-NS AID) based on lecithin oil which has been tested for gastrointestinal toxicity. The three blends tested included lecithin oil in combination with aspirin, indomethacin and ibuprofen. In this study, aspirin was combined with Phosal 35 SB, a soy lecithin oil containing 35 % phospholipid choline, and an aspirin dose of 18 to 54-1353853 g/kg. From the stomach to the fasted rats, the weight ratio of NSAID: lecithin oil is systematically varied from 1:0.5 to 1:1' to 1:2. In addition, other groups of mice received the same dose of aspirin in the absence of lecithin oil, or received the same dose of saline. After forty-five minutes, all animals were challenged with 1 ml of 0.6 N hydrochloric acid from the stomach. After 15 minutes, the animals were euthanized, their stomachs were opened, and the gastric lesions were scored by established methods. 5()·52

As shown in Figure 1, the data confirmed that rats treated with all three aspirin: lecithin complexes were compared to the high number of gastric lesions observed in the aspirin-only mice alone. Only a significant number of gastric lesions were present. To estimate non-aspirin non-steroidal anti-inflammatory drugs (NS AID), indomethacin and ibuprofen, use another ulcer model as previously described. Taking gastrointestinal bleeding as the end point. In this model, NSAIDs were administered intragastrically to fasted rats, either alone or in combination with lecithin oil # Phosal 35 SB in a weight ratio of 1:1 NSAID:lecithin. Control rats received the same amount of saline. In order to make the rats more sensitive to the gastrointestinal damage effect of NS AID, all rats were also injected with nitric oxide (NO) synthetase inhibitor during the 18- to 20-hour study period. L-NAME (20 mg) / kg) three times, after which the animals were euthanized, and the gastrointestinal tract was washed 20 ml with 2 ml of saline, and then the effluent was collected for hemoglobin analysis as an index of gastrointestinal bleeding. The results of these experiments are shown in Figures 2 and 3 below. Referring now to Figure 2, the data confirmed that anti-inflammatory citrate-55-1353853 (indomethacin), at the dose of ι〇 mg / kg, induced a serious increase in gastrointestinal bleeding in rats, this phenomenon can be equally administered by the stomach The dose of anti-inflammatory anti-inflammatory acid but the anti-inflammatory noisy acid system was significantly reduced with Phosal 35 SB in combination with a 1:1 NSAID: lecithin weight ratio.

Referring now to Figure 3, the data confirm that ibuprofen (which is considered to be one of the least toxic non-steroidal anti-inflammatory drugs in the rodent model system) is at a dose of 100 mg/kg. It induces a moderate increase in gastrointestinal bleeding in mice. This phenomenon can be achieved by administering the same dose of ibuprofen from the stomach but the ibuprofen system is combined with Phosal 35 SB in a weight ratio of 1:1 NSAID: lecithin. Significantly lower.

The previously described method was then used to estimate the anti-inflammatory/analgesic activity of the N S AID: lecithin blend (compared to the use of non-steroidal anti-inflammatory drugs (NSAIDS) alone). This was achieved by injecting 1 ml of Froude's Complete Adjuvant (CFA) into the left hind paw of the rat to induce an acute inflammatory response. Four days later, a non-steroidal anti-inflammatory drug (NSAIDS) (aspirin, anti-inflammatory citrate or ibuprofen) was used alone or with Phosal 35 SB at a 1:1 NS AID: lecithin ratio (only Aspirin also estimates other ratios) combined with intragastric administration to rats that were fasted overnight. Two hours later, the rat's sensitivity to stress was measured using Randall-Sellito technique (55). This is done by applying increasing pressure to the inflamed claws or to the contralateral uninflamed claws until the first signs of pain appear in the animal (sounding or stretching of the toes on the hind paws). It is set as the pain threshold for rats. Therefore, low pain and pain are extremely sensitive to stress, while an increase in pain represents low pain sensitivity or represents pain relief. The results are shown in Figure 4-6. -56- 1353853 Referring now to Figure 4, the data confirms that aspirin, at a dose of 10 mg/kg, has the ability to moderately increase the pain threshold of the affected paw in rats, • and the same dose of aspirin When administered in combination with lecithin, the analgesic activity was significantly enhanced at all of the tested weight ratios. Referring now to Figure 5, the data confirm that ibuprofen, at a dose of 25 mg/kg, has an insignificant but modest increase in the ability of the inflammatory paws of the rats to be painful, and the same dose When the ibuprofen Φ acid was combined with the lecithin oil in a weight ratio of 1:1, the analgesic activity was significantly enhanced. Referring now to Figure 6, the data confirms indomethacin at a dose of 4 mg/kg. The data show that the mushy composition provides improved pain management activity compared to unmodified inflammatory tannic acid and has a greatly improved pain management activity compared to the control saline. # Non-steroidal anti-inflammatory drugs (NSAIDS) and central and peripheral nervous system trauma and injury inflammation are acute traumatic injuries to the central nervous system such as spinal cord injury (SCI) [A1] and with delayed neurodegenerative diseases such as Azi Each of the key components of progressive pathophysiology is related to Herm's disease (AD) [A2]. The inflammatory process is thought to be directly responsible for, or contribute to, the motor function and chronic pain development often observed in spinal cord injury (SCI) and the loss of memory and cognitive function observed in Alzheimer's disease (AD). Progressive deterioration. Recently, the use of anti-inflammatory drugs has been shown to attenuate tissue loss and dysfunction in a rodent-57- 1353853 model of traumatic spinal cord injury [A3].

Even more noteworthy is the recent epidemiological study that the long-term consumption of non-steroidal anti-inflammatory drugs (NSAIDS) can reduce the risk of Alzheimer's disease (AD) by up to 50% [A4] ]. It is conceivable that when a transient or long-term NSAID treatment strategy is used depending on the nature of the inflammatory condition, it is difficult to make the non-steroidal anti-inflammatory drug (NS AIDS) effective at low doses with minimal side effects and adequately tolerated. It is well established that about 40% of people in the country develop gastrointestinal (GI) symptoms due to long-term consumption of NSAIDs, ranging from indigestion to life-threatening gastric ulcers and bleeding [A5].

In 995, PI's laboratory report stated that in addition to inhibiting the activity of cyclooxygenase (COX), non-steroidal anti-inflammatory drugs (NSAIDS) also have the ability to attenuate the hydrophobic barrier of the upper digestive tract, most likely by Chemically associated with the surface lining of phospholipids [A6]. In addition, we have demonstrated that in laboratory animals and humans, if the non-steroidal anti-inflammatory drug (NSAID S) is combined with the most famous phospholipids, it is synthesized or in the form of purified extracts (eg from soy lecithin). (PC), when chemical association is performed, shellfish [J can avoid the damaging effects of non-steroidal anti-inflammatory drugs [A6, A7]. Interestingly, we have also confirmed that in addition to their low gastrointestinal toxicity, phospholipid choline-non-steroidal anti-inflammatory drugs (PC-NS AIDS) also have an increase in membrane permeability and cyclooxygenase (COX) inhibitory activity. It also has a medical activity that enhances the inhibition of fever, inflammation and pain [A6, A8, A9]. Oral administration of phospholipid choline-isobuprofen (PC-ibuprofen) reduces inflammation-dependent dependence on peripheral nerve ligation. Development of hyperalgesia -58- 1353853 It has been reported that placing four loose chromic intestinal lines around the sciatic nerve will induce the affected nerves to produce severe peripheral nerve inflammation, and as if applied to the ipsilateral side The pressure on the paws and the hyperalgesia caused by heat show that neuropathic pain will be induced after 2-4 days of surgery [A10, All]. The effect of the treatment of phospholipid choline-non-steroidal anti-inflammatory drugs (PC-NSAID) on peripheral nerve inflammation and hypoalgesia is performed using this inducing technique φ in mice. This rodent model is used to induce nerve inflammation in the right or left sciatic nerve. Sham surgery is performed on the opposite side. Two days after surgery, the rats were randomly divided into the following experimental groups (12 rats/group); saline control group; ibuprofen (ibupr〇fen) (15 mg/kg; and phospholipid choline-isobutylbenzene) Propionate (PC-ibuprofen) (same dose of NSAID). The tested NSAID blend was administered to the rats twice a day for two days and the pain of the two hind paws was analyzed before and after the two days of administration. Some of the behavioral indices. The behavioral analysis used to analyze efficacy is: the defensive behavior of the affected hind paws; the potential φ of the claws on the heat withdrawal; and the paw withdrawal response to the von-Frey hair stimulating effect And the pain response after pressure applied to the hind paws [A8]. At the time of euthanasia, the ligation-and-control nerves were dissected for visual inspection of the inflammatory index by the naked eye and histology. These results show that in the hind paw In the model of inflammation (induced by Froend's adjuvant), the analgesic activity of phospholipid choline-ibuprofen was significantly greater than that of ibuprofen alone, and Like measuring the stimulating effect on von-Frey hair and the claws of heat Phosphocholine-i-amphetamine is also effective in reducing the pain sensitivity caused by sciatic nerve ligation. -59- 1353853 Oral administration of phospholipid choline-ibuprofen (PC- Ibuprofen) reduces tissue loss, action function, and attenuates the development of chronic pain syndrome in a rat model of contusive spinal cord injury

Recently, delivery of a single dose of an anti-inflammatory drug has been shown to reduce the size of spinal cord lesions in adult rats [A3]. Compared to untreated mice, these non-steroidal anti-inflammatory drugs (NS AID) treated mice exhibited greater mobility and reduced hyperalgesia and mechanical-touch pain (contact-induced pain). Symptoms, characteristics of neuropathic pain. The development of chronic, neuropathic pain is a very common occurrence after spinal cord injury and can be a permanent burden for patients. There is an extreme need for effective treatments that are well tolerated to avoid or attenuate the development of chronic central pain. Oral administration of phospholipid choline-non-steroidal anti-inflammatory drugs (PC-NS AIDS) reduces tissue damage, improves outcomes, and avoids chronic pain syndrome associated with spinal cord injury.

Is a more effective than ibuprofen to reduce the pathophysiology of Azheimer's disease in the gene transfer mouse model of Alzheimer's disease. Recent clinical evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDS) can significantly reduce the risk of Alzheimer's disease. The main problem in designing a treatment strategy for Alzheimer's disease is the lack of adequate animal models. The recently established human/3-amyloid-over-expressed Tg2576 squirrel provides confirmation of age-dependent memory, cognition, and histopathological loss including amyloid plaque formation, microglial activation, and star cell reactivity And dystrophic -60-1353853 Convenient animal model of neuritis [A19-A21]. Ibuprofen has recently been shown to reduce amyloid plaques, dystrophic neuritis and activating glial glials in the Tg2576 _ murine Alzheimer's model [A21]. The ideal period of application of phospholipid choline-non-steroidal anti-inflammatory drugs (PC_NSAIDS)

Successfully commercialized phosphocholine-non-steroidal anti-inflammatory drugs (PC-NSAIDs) require a long-term stable formulation at room temperature. Although not a problem for most non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, it is true for aspirin, which rapidly hydrolyzes into poplar if exposed to water. acid. The compositions of the present invention are based on a non-steroidal anti-inflammatory drug (N SAID) which is soluble and/or dispersed in a non-aqueous carrier comprising phospholipids such as lecithin oil or any other biocompatible raw oil. Because this environment is hydrophobic, it enhances the stability of aspirin in aspirin-based blends. Experimental results of trauma and injury to the central and peripheral nervous system These experiments confirmed that phospholipid choline-ipulphonic acid (PC-ibuprofen) is an effective therapeutic agent for spinal cord injury (SCI). The results showed that rats treated with 25 mg N SAID/kg body weight were administered twice daily for up to 6 weeks after spinal cord injury (SCI). Referring to Figures 7A and 7B, the data shown in the graph confirm that spinal cord injury (SCI) causes hyperalgesia in the rat, which is like a ridge that will be treated with saline [S] -61 - 1353853

Myeloidally injured rats were confirmed by a reduction in pain threshold as measured by Randall-Sellito technique. In contrast, hyperalgesia due to spinal cord injury was not seen in spinal cord injury (SCI) rats treated with ibuprofen or phospholipid acetylcholine-isobufenic acid (PC-ibuprofen). Phosphocholine-isobuprofen (PC-ibuprofen) appears to be superior to unmodified ibuprofen. This information is presented in two ways. In Figure 7A, the data is directly plotted (unnormalized) according to the record, while in Figure 7B, the data for each animal is compared to its own pre-operative baseline. This graphical representation of the data may be the most convincing of the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) after spinal cord injury (SCI).

Referring now to Figure 8, the excellent analgesic activity of phospholipid acetylcholine-isobufenic acid (PC-ibuprofen) in spinal cord injury (SCI) mice was also confirmed in the second behavioral test, which measured the increase in hind paws. % of the reaction produced by the stimulating effect of the diameter fiber (von Frey) hair (which is equivalent to the force). Please note that in this case, the lower number represents pain relief, while in the Randall-Sellito trial, pain is indicated by a higher pain stress. Referring now to Figure 9, the evidence shows that, unlike the rats treated with saline or phospholipid choline-ibuprofen, ibuprofen-treated rats were studied for 6 weeks. No weight gain during the period. This suggests that spinal cord injury (SCI) rats may have a mild toxic response to ibuprofen alone, which may also be due to blood urea nitrogen (representing nephrotoxicity) and lactate dehydrogenase (LDH, representing the liver). Shown by a slight increase in toxicity). -62- 1353853 Referring now to Figure 10, the evidence is not as 'as estimated by the established BBB trial, the recovery of motor function after spinal cord injury (SCI) is in the absence of benziprofen (ibuprofen) The rats were weakened, and there was no difference in the motor function recovery index between the saline and the disc lipid choline-isobuprofen (PC-ibuprofen) group. Phosphocholine-non-steroidal anti- φ inflammatory drugs (PC-NSAIDS) as effective blends for the treatment of thrombotic disorders. Blends of the invention, including phospholipids such as phospholipid choline (PC) and non-steroidal anti-inflammatory drugs (N SAID), Aspirin in biocompatible oils is an effective blend for the treatment of thrombotic disorders including thrombosis, stroke and myocardial infarction. In addition to improving gastrointestinal safety, phospholipid choline-aspirin is a more potent inhibitor of platelet aggregation and blood stasis than regular aspirin. Aspirin (ASA) is chemically associated with zwitterionic phospholipids to form an associative complex. It has the same or enhanced activity to reduce fever, pain and inflammation than the original # aspirin, but no Aspirin has severe gastrointestinal side effects of ulcers and bleeding. Interestingly, phospholipid-associated aspirin is more effective in the in vivo model of arterial thrombosis than aspirin alone to prevent thrombus formation. Therefore, the phospholipid choline-aspirin complex of the present invention inhibits platelet aggregation and thrombosis, and causes symptoms of a thrombus lowering condition. Thrombotic arterial occlusive diseases such as myocardial infarction (MI) and stroke are the leading causes of death in the United States and Western societies. According to the American Heart Association, more than one million Americans will suffer from acute myocardial infarction in the coming year. Therefore, it can effectively reduce ί -63- 1353853

Drugs for arterial thrombosis have great clinical importance. Because thrombosis is the decisive process for the initiation and spread of arterial occlusive disease, it is the reason for the development of novel, specific antithrombotic drugs. Arterial embolization is a complex process involving a series of cellular and biochemical interactions between blood cells, blood vessel walls and plasma proteins (B 1). Platelets play a central role in these interactions (B 2). It adheres to the damaged vessel wall and undergoes cell activation, secretion and assembly. Activated platelets can accelerate the coagulation of blood, and the molecules secreted by them can promote the proliferation of vascular smooth muscle cells. In view of the central role of platelets in arterial thrombosis, the efforts of several years have mainly been based on the inhibition of platelet function. Antithrombotic drug (B 3). However, few compounds are clinically useful. In fact, aspirin is still the main drug and prototype antiplatelet agent for clinical use based on its efficacy and cost. It is effective in preventing major and minor myocardial infarction and stroke (B4-B 7). However, there is still uncertainty about the optimal medical dosage form for aspirin, and more than 40% of patients with gastrointestinal toxicity cannot use aspirin or even enteric-soluble aspirin. Of particular relevance is the recent report that even very low doses of aspirin (10-80 mg) induce a significant number of patients to induce gastric erosion and bleeding. This can be explained as the current largest group of gastrointestinal bleeding inpatients who are chronically taking low doses of aspirin to reduce the risk of cardiovascular disease (B 8). Aspirin and other non-steroidal anti-inflammatory drugs (N SAIDS) have long been known to inhibit the synthesis of prostaglandins. Two isoforms of cyclooxygenase, COX-1 and COX-2 have been described and non-steroidal anti-inflammatory drugs (NSAIDS) block the activity of these two cyclooxygenase isoforms (B9--64- 1353853 B 12). Aspirin blocks the production of thromboxane A2 (TXA2) by inhibiting the activity of COX-1 in platelets, thereby exhibiting its antiplatelet effect. -· However, aspirin also inhibits the same enzymes in the vascular endothelium, thus preventing the production of prostaglandin (PGI2) (B13, B14). This inhibition of endothelial epoxidase accelerates the progression of thrombosis and atheroma hardening, and is called "aspirin dilemma", which is one of its shortcomings in clinical use. This dilemma leads to the use of low-dose aspirin, which inhibits the production of thromboxane Φ a2 (txa2), while the remaining prostacyclin (pgi2) provides optimal antithrombotic conditions to reduce platelet aggregation. Can keep the blood vessels dilated. Therefore, the ratio of prostaglandin (pgi2) to thromboxane a2 (txa2) is deeply involved in the treatment of restless angina, myocardial infarction, transient ischemic attack, and stroke. Using appropriate presing, blending, and delivery rates, 'aspirin may prevent the production of platelet thromboxane a2 (txa2) while minimally interfering with the production of vasopressin (PGI2) (B15-B17) ).

Non-steroidal anti-inflammatory drugs (NS AID) for the treatment and/or prevention of thrombosis. Non-steroidal anti-inflammatory drugs (NS AIDS), including aspirin is the most severely consumed drug in the country and because of this group of drugs for treating fever, pain And the vast effect of inflammation, so its dosage has increased exponentially over the past decade (B18). Recent evidence suggests that individuals who have long-term intake of aspirin develop a lower rate of cardiovascular disease (narrow heart disease, myocardial infarction, thrombosis, and stroke) than the average person's population, which leads to an increase in the number of self-administered drugs. Spilling sells 3 5 - 40% of the total annual sales (B 1 9). As a result, it is estimated that there is about 1% -65 - 1353853

The people of the country take aspirin daily. As a result, the Food and Drug Administration (FDA) now recognizes the use of aspirin to reduce the risk of stroke, angina and heart attack. However, there is still uncertainty about the optimal medical dose for aspirin. One of the barriers to index increase in the use of non-steroidal anti-inflammatory drugs (NSAIDS), which is expected to continue with the increase in the average age of the country, for which ethnic compounds can induce significant side effects, most commonly Gastrointestinal bleeding and ulcers (B 2 0). Of particular relevance is the recent report that even very low doses of aspirin (10-75 mg) induce gastric erosion and bleeding in humans (B 8).

The dose of aspirin can be considerably reduced by association with a zwitterionic phospholipid such as phospholipid choline, so that the drug advantage: the risk ratio significantly improves the prostacyclin (PGI2), phospholipid-coincidence relative to blood vessels Aspirin selectively inhibits the production of platelet thromboxane A2 (TXA2), and it is conceivable that the phospholipid/aspirin complex is compared to the effect of uncoordinated aspirin. These differential effects on platelet and endothelial cyclooxygenase activity are important in enhancing antithrombotic activity. This observation can be used to prevent thrombosis and vascular occlusion throughout the experiment by low-dose phospholipid-associated aspirin in a living model of arterial thrombosis, while this subcutaneous dose of aspirin is used alone. Further support was obtained by preventing the occurrence of thrombosis and vascular occlusion within one hour. It is also important to emphasize that the other advantage of phospholipid choline-aspirin is that it produces significantly less gastric mucosal damage than regular aspirin and therefore has no side effects and acts as The development of an effective antithrombotic phospholipid choline-aspirin complex will have a broad, cost-effective clinical application price of 66- 1353853. The main researcher - the results of the study:

In 1995, Lichtenberger and his associates (B21) reported that in the mouse, if the drug is pre-associated with the purified palm phosphatidylcholine (DPPC), synthetic phospholipids or soy lecithin, it is because of oral administration. Puling and some other non-steroidal anti-inflammatory drugs (NSAIDSK including Diclofenac 'indomethacin, naproxen) can significantly reduce the effects of acute gastrointestinal injury. Recently, the inventors reported (B2 2) pre-double-blind, cross-clinical results, in which 16 healthy volunteers were orally administered aspirin or mismatched phospholipids during the four-day study period. Aspirin of choline (650 mg, three times a day), and the degree of mucosal damage was estimated by image endoscopy. As shown in Figure 11, the phospholipid choline-aspirin complex reduces the number of gastric erosions in susceptible individuals compared to the same dose of unmodified aspirin. Up to 70%. This reduction in gastric toxicity is independent of changes in the cyclooxygenase (COX) inhibitory activity of the drug. As shown in Figure 12, both aspirin and phospholipid choline-aspirin have > 85% of the equivalent inhibition of the activity of the treasure ring oxidase (COX). The inventors' laboratory also reported (B 23) that when a non-steroidal anti-inflammatory drug (N SAID) is chemically associated with phospholipid choline, aspirin inhibits fever, inflammation, and pain in mice. Medical activity is consistently enhanced, and its medical performance is 5-1 times higher than the unmodified NS AID. Other studies using rodent rodents have also confirmed that if the drug and phospholipids

-67- 1353853 When choline is chemically associated with intragastric administration, the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit joint inflammation and pain is enhanced.

In vitro in animal studies - study phospholipid choline-aspirin (PC-asp ir in) complex (containing two molar concentrations of the two preparations) in the platelets and vascular tissue to produce thromboxane The ability of A2 (TXA2) and prostacyclin (pgi2). The rats were administered intragastrically without modified and dipalmitoside phosphocholine (DPPC)-associated aspirin (20 mg/kg dose). After 30 minutes, blood was drawn to prepare platelet-rich plasma. And then arachidonic acid induced assembly. Reduced productivity of TXB2 (a stable metabolite of TXA2) in platelets of rats treated with unmodified aspirin or dipalmitoside phospholipid (DPPC)-aspirin, respectively, compared to the saline control group . As shown in Figure 13A, phospholipid choline (PC)-aspirin further inhibits the production of TXB2. This in vitro method is in turn used to measure prostaglandin (PGI2) of blood vessels (endothelial). The abdominal aorta, which was excised after administration of the drug, was incubated with arachidonic acid (AA, 25 mM) to estimate its ability to produce 6-keto PGFla% (a stable metabolite of PGI2). As shown in Figure 13B, aspirin significantly inhibited the production of 6-keto PGFla compared to the control group, while dipaltophosphatidylcholine alone (DPPC) or mismatched aspirin The second palm phosphatidylcholine (DPPC) has no effect. Therefore, by administering phosphocholine (PC)-aspirin or permitting, it is possible to selectively inhibit platelet epoxidase and preserve vascular prostacyclin biosynthesis. The antithrombotic effect of aspirin with or without phospholipid in an in vivo model of arterial blood sputum production is then estimated. According to the proposed case (B 24), the left carotid artery of the hemp-68-1353853 drunk rabbit received an anodic current to achieve a point where the average carotid blood flow rate was increased by 50% compared with the control sputum, which was equivalent to the thrombus formed. Make -· blood vessels have 50% occlusion -. At this point, the current is interrupted, and the test drug administered intravenously by blood flow is monitored for the next 2-3 hours. As can be seen from Fig. 14A, in control rabbits treated with saline or phospholipid choline alone, the carotid blood flow rate decreased to zero within < 60 minutes (average time to occlusion = 40 ± 17). In contrast, rabbits who had not been modified with A. spirulina had a dose range of 5-20 mg/kg, and there was no vascular occlusion during the entire 2-3 hour experiment (data not shown). Interestingly, as shown in Figure 14A, when the dose of aspirin was reduced to 2.5 mg/kg, aspirin, which is mismatched with phospholipids, is still effective in preventing thrombus formation (after administration of the complex) &gt 180 minutes), while using aspirin alone (at this threshold dose) did not prevent thrombus formation and occlusion of the vessel within 61 ± 15 minutes (n = 4). Moreover, as shown in Figure 14B, the thrombus weight formed in rabbits given 2.5 mg/kg dose of aspirin-phospholipid complex was significantly smaller than that of the original aspirin, saline or phospholipid alone. Processor. The concentration of 6-keto PGFia (a stable metabolite of PGI2) and thromboxane A2 (TXA2) was also measured in the affected carotid artery. In the saline control group, the ratio of 卩012 to txa2 in the affected artery (where thrombus was formed) was significantly lower (because the production of thromboxane B2 (TXB2) increased) unaffected carotid artery (they were not Produces a thrombus). When rabbits were treated with aspirin alone (2.5 mg/kg) or phospholipids, this ratio of PGI2 to TXA2 increased slightly, but was not sufficient to block thrombus formation. In contrast, as shown in Figure 1 4C, t S 3 -69-1353853, the PGI2/TXA2 ratio of rabbits receiving the same dose of phospholipid choline (pc)·aspirin was significantly increased and treated with saline. There was no significant difference in the ratio measured in the normal arteries of rabbits (not exposed to the anodic current). Phosphocholine (PC)-p-acetamidophenol 0 (^13111丨11〇?1^11) blend

Figure 15 is a graphical representation of a 24-hour challenge from a fasting Sprague Dawley rat by Tylenol alone or with a combination of acetaminophen (Tylenol): P3 5 SB. After that, the degree of increase in the concentration of liver enzyme aminotransferase (AST) showed that 1:2 ratio of acetaminophen (Tylenol): P35 SB can protect rats from liver damage. . The data showed that by using some statistical tests, the Tylenol-treated aspartate aminotransferase (AST) 値 appeared to have a significant increase compared to the saline control group, but the ratio of 1:2 by Tylen〇 l: The mouse of the P35 SB combination is not.

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B20. Gabriel SE, Jaakkimainen R, Bombardier C. Risk for serious gastrointestinal complications related to the use of nonsleroidal anli-inflaminatory drugs. Ann Int Med 115: 787-796, 1991* B2I. Lichtenberger LM, Wang ZM, Romero JJ, Ulloa C5 Perez J, Giraud MN, Barreto JC. NSAIDs associate with zwitterionic phospholipids: Insight into the mechanism and reversal of NSAID-induced GI injury. Nature Medicine Γ.154-158, 1995. B22. Anand BS, Romero JJ5 Sanduja SK , Lichtenberger LM. Evidence that phospholipid reduces the gastric loxicily of aspirin in human subjects. Am J Gastroenterol 94: 1818-1822, 1999. B23. Lichtenberger LMS Ulloa C, Vanous AL, Romero JJ, Dial EJ, lllich PA, Walters ET ZwiUei ionic phospholipids Enhance aspirin's therapeutic aclivily, as proven in rodent

-79- 1353853 model systems. J Pharm ExpTherap 277:1221-1227, 1996. B24. Benedict CR, Refino CJ, Keyt BA, Pakala R, Paoni NF, Thomas R, Bennett WF. New variant of human tissue plasminigen activator (TPA Circulation 92: 3032-3040, 1995. B25. Blake PR, Summers MF. NOESY-1*1 Ech spectroscopy with eliminated radiation damping. J Magn Res 86: 622 -625, 1990. B26. Pinon JF. In vivo study of platelet aggregation in rats. J Pharmaco Methods 12:79, 1984.

B27. Triplett DA, Harms CS, Newhouse P, Clark C. Platelet Function: Laboratory evaluation and clinical application. Edited by Triplett DA. American Society of Clinical Pathologists, Chicago, 1978. B28. Sanduja SK, Mehta K, Xu XM, Sanduja R and Wu KK. Differentiation associated expression of prostaglandin H and thromboxane A synthases in monocytoid leukemia cell lines. Blood 78:3)78-3185, 1991. B29. Sanduja SK, Tsai AL? Aleksic NM, Wu, KK Kinetic of Prostacyclin Synthesis In PGHS-1 Overexpressed Endothelial cells. AwJ.PhysioL 261: C1459-1466, 1994. B30. Gambino MC, Cerlelti C, Marchi S, Garattini S, Gaetano GD. How intravenous administration of low dose aspirin inhibits both vascular and platelet cyclooxygenase activity : an experimental study in the rats. Expt Bio Med 182:287, 1986.

B31. Pierangeli SS, Barker JH3 Stikovac D, Ackerman D, Anderson G, Barquinero J, Acland R, Harris EN. Effect of human IgG anliphospholipid antibodies on an in vivo thrombosis model in mice. Thromb Haemost 71: 670-674, 1994. D32. Edwards MH, Pierangeli S, Liu X, Barker JH, Anderson G, Harris EN. Hydroxychloroquine reverses Ihrombogenic antibodies in mice. Circulation 96: 4380-4384, 1997. B33. Pierangeli SS, Liu X, Antonov JT, Sparrow JT, Harris EN, Myones BL. Induction of pathogenic anticardiolipin antibodies in a murine model. Arthritis Rheum 41: SI 35, 1998. B34. Myones BL, Antonov IV5 Fedorova LI, Volgin AY, Liu X, Espinola R, Harris EN, Pierangeli SS. Complexes of protein and saturated cardiolipin are capable of binding -80- 1353853 antiphospholipid antibodies and inducing thrombogenic antiphospholipid antibodies in a murine model. Arthritis Rheum 42: S369, 1999. - End of all references cited herein for inclusion in reference. Although the present invention has been fully and fully described, the present invention may of course be practiced other than the specific method φ within the scope of the appended claims. Although the present invention has been described with respect to the preferred embodiments thereof, those skilled in the art can understand that the present invention can be carried out without departing from the scope and spirit of the invention as described in the following claims. ALTERNATIVE AND IMPROVEMENT [Brief Description] The present invention will be more apparent from the following detailed description and the accompanying drawings.

Figure 1 demonstrates that, unlike the high number of gastric lesions observed in mice that were only administered aspirin (ASA), the ASA:LEC weight ratio was approximately 1:0.5, 1:1, and approximately 1:2. Aspirin: Lecithin (LEC, using lecithin oil, Phosal 35 SB) blends treated mice with significantly fewer gastric lesions; Figure 2 confirms that anti-inflammatory citrate, at 10 mg/kg At doses, it can induce a severe increase in gastrointestinal bleeding in rats, which can be achieved by intragastric administration of the same dose of anti-inflammatory niacin combined with Phosal 35 SB (NSAID: lecithin weight ratio of 1:1) Significantly lower. -81 - 1353853 Figure 3 demonstrates that ibuprofen (which is considered a conventional NSAID with minimal toxicity to rats) induces moderately increased gastrointestinal bleeding in rats at a dose of 100 mg/kg. The phenomenon can be significantly reduced by administering the same dose of ibuprofen in the stomach in combination with Phosal 35 SB (NSAID: lecithin weight ratio of 1:1).

Figure 4 demonstrates that aspirin, at a dose of 10 mg/kg, has the ability to moderately increase the pain threshold of the affected paw in rats, whereas when the same dose of aspirin is combined with lecithin oil (in At all test weight ratios, the analgesic activity of aspirin was significantly increased; Figure 5 demonstrates that ibuprofen has a moderate but insignificant increase in pain in the affected paw at 25 mg/kg. The ability of the pressure threshold, however, when the same dose of ibuprofen and lecithin oil were combined in a weight ratio of 1:1, the analgesic activity of ibuprofen was significantly increased;

Figure 6 demonstrates that anti-inflammatory citrate, at a dose of 4 mg/kg, has a moderate but insignificant increase in the pain threshold of the affected paw in rats, whereas when the same dose of anti-inflammatory citrate and lecithin When the oil is administered in combination with a weight ratio of 1:1, the analgesic activity of anti-inflammatory niacin is significantly increased; Figure 7A is a graph showing the hyperalgesia induced by spinal cord injury (SCI) by phospholipid choline-different Information on the reversal of tympanic acid (?(:-1131^1'〇&11) and Ibuprofen); Figure 7B is a diagram showing the involvement of spinal cord injury (SCI) Hyperalgesia is reversed by treatment with phospholipid choline-ibuprofen (Ibuprofen) and ibuprofen; Figure 8 is a graphical representation of phospholipid choline-isobutylbenzene Propionic acid (PC- -82- 1353853

Ibuprofen) and Ibuprofen (Abuprofen) data on analgesic activity after 5 weeks of spinal cord injury in rats; Figure 9 is a graphical representation of the related phospholipid choline-isobuprofen (PC-Ibuprofen) and isobutylbenzene Weight gain data for rats with spinal cord injury treated with propionate (Ibuprofen) during 6 weeks; Figure 10 is a graphical representation of spinal cord injury (SCI) via phospholipid choline-ibuprofen and isobutylbenzene Information on the recovery of motor function after treatment with propionate (Ibuprofen); Figure 11 is a graphical representation showing that phospholipid choline-aspirin complex is significant compared to the same dose of unmodified aspirin The number of gastric lesions in individuals with reduced susceptibility is 70°/. Moreover, the decrease in gastric toxicity is independent of the change in the C0X inhibitory activity of the drug. Figure 12 is a graph showing that both aspirin and phospholipid choline-aspirin have the same ability to inhibit sinus COX activity by > 85%. Figures 13A and 13B are graphs showing the concentration of TXB2 in rat platelets 30 minutes after oral saline, DPPC, ASA (20 mg/kg), or ASA with DPPC mismatched. PRP was prepared first, and then AA (2 mM) was used to induce aggregation. TXB2 is measured using radioimmunoassay (RIA). The results are expressed as mean SEM; n = 3. * = p < 0.05 0 pairs ASA - abbreviations: DPPC = di-brown phosphatidylcholine; AA = arachidonic acid; PRP = platelet-rich plasma; TXB = thromboxane; Figure 13B is a schematic representation of 20 The effect of mg/kg ASA on 6KPGFla produced by the abdominal aorta alone or in combination with DPPC in the stomach. After 1 hour, move the aorta out and then each master

Claims (1)

1353853 Annex 5A No. 0981 16729 Application for Patent Scope Amendment Ϊ Republic of China | 1 (3⁄4 years 4 Poverty Day Amendment VII. Patent Application Scope 1. A substantially non-aqueous composition for reducing gastrointestinal side effects of a non-steroidal anti-inflammatory drug (NSAID) comprising a phospholipid-containing non-aqueous carrier mixed with a therapeutically effective amount of a powder form non-steroidal anti-inflammatory drug (NS AID) Wherein the weight ratio of the NSAID to the carrier is from about 1 :1 to 1:10, and the phospholipid is a combination of dipalmitoside phosphocholine or dipalmitoside phosphocholine and phospholipid choline, and wherein the phospholipid-containing The non-aqueous carrier is a lecithin oil containing from about 20 to about 60% by weight of dipalmitoside phosphocholine (DPPC), or a combination of phospholipid choline (PC) and DPPC. 2. The composition according to claim 1, wherein the weight ratio of the NSAID to the carrier is between about 2:1 and about 1:1. 3. The composition according to claim 1, wherein the non-steroidal anti-inflammatory drug (NSAID) is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac ( Diclofenac), anti-inflammatory B-indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozin, ketorolac ), sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone ), phenylbutazone, celecoxib, rofecoxib, a COX2 inhibitor, acetaminophen, or a mixture or combination thereof. The composition according to any one of claims 1 to 3, wherein the phospholipid reduces gastrointestinal toxicity of the non-steroidal anti-inflammatory drug (N SAID) 〇 5. According to the scope of claims 1 to 3 a composition wherein the composition increases the treatment/prevention of non-steroidal anti-inflammatory drugs (NSAIDs), inflammation, fever, cardiovascular disease, ovarian cancer, colon cancer, and/or medical treatment of Alzheimer's disease Activity and / or efficacy. 6. A method of preparing a substantially non-aqueous formulation comprising a non-steroidal anti-inflammatory drug (NS AID) comprising adding an effective amount of a powder form of a non-steroidal anti-inflammatory drug (NS AID) to a non-phosphorus a step of forming a non-aqueous solution, paste, semi-solid, suspension, dispersion, colloidal suspension or mixture thereof in an aqueous carrier, wherein the weight ratio of NS AID to carrier is from about 10:1 to 1:10, And the phospholipid is dipalmitoside phosphocholine, or a combination of dipalmitoside phosphocholine and phospholipid choline, and wherein the phospholipid-containing non-aqueous carrier is a dipalmitolipid phospholipid containing a concentration of about 20 to about 60% by weight. Lecithin oil in combination with a base (DPPC), or phospholipid choline (PC) and DPPC. 7. The method of claim 6, wherein the weight ratio of the NSAID to the carrier is between about 2:1 and about 1:1. 8. The method according to claim 6, wherein the non-steroidal anti-inflammatory drug (NSAID) is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac , indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozin, 1353853 ketorolac, Sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, hydroxybutazone. ), phenylbutazone, celecoxib, r〇fec〇xib, a C0X2 inhibitor, acetaminophen, or a mixture or combination thereof. 9. A composition comprising φ aqueous emulsion and microemulsion comprising an aqueous phase and a non-aqueous phase and any emulsifier, wherein the aqueous phase is a biocompatible aqueous solution and the non-aqueous phase comprises a non-aqueous carrier containing phospholipids and optionally A medically effective amount of a powder form non-steroidal anti-inflammatory drug (NS AID) wherein the phospholipid is present in an amount sufficient to prevent or reduce tissue ulceration and, when present in the NS AID, in an amount sufficient to reduce the pathogenic effect of the NS AID Wherein when the NS AID is present, the weight ratio to the carrier is from about 10:1 to 1:10, and the phospholipid is a combination of dipalmitoside phosphocholine or dipalmitoside phosphocholine and phospholipid choline, and The non-aqueous carrier containing the phospholipid is a lecithin oil containing a combination of dipalmitoside phosphocholine (DPPC) having a concentration of φ of about 20 to about 60% by weight, or a combination of phospholipid choline (PC) and DPPC. 10. The composition according to claim 9 wherein the weight ratio of the NSAID to the carrier is between about 2:1 and about 1:1. 1 1. The composition according to claim 9 wherein the non-steroidal anti-inflammatory drug (NS A ID) is selected from the group consisting of aspirin, salicylate, naproxen, diclofen Acid (diclofenac), indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozin, -3- 1353853 Ketorolac, sulindac 'nabumetone, meclofenamic, piroxicam, diflunisal, diflunisal Oxyphenbutazone, phenylbutazone, celecoxib, rofecoxib, C0X2 inhibitor, acetaminophen, or mixtures or combinations thereof . 12. The composition according to any one of claims 9 to 11, wherein the phospholipid lowers the gastrointestinal toxicity of the non-steroidal anti-inflammatory drug (NS AID). 1 3 according to the scope of the patent application ninth to eleventh Any of the components, wherein the composition increases the treatment of non-steroidal anti-inflammatory drugs (NSAIDs) / prevents inflammation, pain, fever, cardiovascular disease, ovarian cancer, colon cancer, and/or Alzheimer's disease Medical activity and/or efficacy. 1 4. The composition according to any one of claims 9 to 1 wherein the composition is a mouthwash or a lotion for oral ulcers and/or inflammation caused by mucositis. And the mouth includes the mouth, gums and teeth. 1 5 . The composition according to any one of claims 9 to 11 wherein the composition is an eye drop or a cleansing agent for treating inflammation of the eye caused by uveitis. The composition according to any one of claims 9 to 11, wherein the composition is a drink for treating oral, esophageal and/or gastrointestinal mucositis. - A method for preparing a substantially non-aqueous 1353853 blend containing a non-steroidal anti-inflammatory drug (NSAID) comprising the steps of: adding a therapeutically effective amount of a powder form of a non-steroidal anti-inflammatory drug (NSAID) to a sufficient amount of phospholipids a non-aqueous composition in the form of a solution, a paste, a semi-solid 'suspension' dispersion, a colloidal suspension or a mixture thereof in a non-aqueous carrier; the non-aqueous composition is then biocompatible In solution, emulsified in the presence or absence of an emulsifier; wherein the weight ratio of NSAID to carrier is from about 10:! to 1:10, and φ the phospholipid is dipalmitoside phosphocholine or dipalmitoside phosphocholine In combination with phospholipid choline, and wherein the phospholipid-containing non-aqueous carrier is an egg having a concentration of about 20 to about 60% by weight of dipalmitoside phosphocholine (DPPC), or a combination of phospholipid choline (PC) and DPPC Phospholipid oil. 18_ The method of claim 17, wherein the weight ratio of the NSAID to the carrier is between about 2:1 and about 1:1. 19. The method according to claim 17, wherein the non-steroidal anti-inflammatory drug (NSAID) is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac (diclofenac), anti-inflammatory citrate (indomethacin) > sulindac, ibuprofen, ketoprofen, oxaprozin, ketorolac ), sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone ), phenylbutazone, celecoxib, rofecoxib, a COX2 inhibitor, acetaminophen, or a mixture or combination thereof. The method of claim 17, comprising the steps of: shearing the emulsified material to form a microemulsion. 2 1 . A substantially non-aqueous pharmaceutical composition for treating inflammation comprising a non-aqueous carrier and the non-aqueous carrier comprising a therapeutically effective amount of a non-steroidal anti-inflammatory drug (NSAID) in powder form and an amount sufficient to reduce the pathogenic effect of NSAID a phospholipid, wherein the weight ratio of NS AID to the carrier is about 1 〇: 1 to 1: 10, and the phospholipid is a combination of dipalmitoside phosphocholine or dipalmitoside phosphocholine and phospholipid choline, and wherein The phospholipid-containing non-aqueous carrier is a lecithin oil containing a combination of dipalmitoside phosphocholine (DPPC)' or phospholipid choline (PC) and DPPC at a concentration of from about 20 to about 60% by weight. 22. The pharmaceutical composition according to claim 21, wherein the weight ratio of NSAID to carrier is between about 2:1 and about 1:1. 23. The pharmaceutical composition according to claim 21, wherein the non-steroidal anti-inflammatory drug (NSAID) is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac ( Diclofenac), indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozin, ketorolac , sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone ), phenylbutazone, celecoxib, rofecoxib, a COX2 inhibitor, acetaminophen, or a mixture or combination thereof. 1353853 24. A substantially non-aqueous pharmaceutical composition for preventing or treating tissue ulceration and/or inflammation comprising a non-aqueous carrier and comprising: any effective amount of a powder form of a non-steroidal anti-inflammatory drug (NSAID) And • a phospholipid sufficient to prevent ulceration and/or inflammation caused by mucositis caused by chemical-and/or radiation therapy, and which is sufficient to reduce the pathogenic effect of NSAID when NSAID is present, wherein when N SAID is present , the weight ratio to the carrier is about 1 〇: 1 to 1: 10, and the phospholipid is a combination of dipalmitoside phospholipid choline, or dipalmitoside phosphocholine and phospholipid choline, and wherein the phospholipid-containing The non-aqueous carrier is a lecithin oil containing from about 20 to about 60% by weight of dipalmitoside phosphocholine (DPPC), or a combination of phospholipid choline (PC) and DPPC. 25. The pharmaceutical composition according to claim 24, wherein the weight ratio is between about 2:1 and about 1:1. 2 6. The pharmaceutical composition according to claim 24, wherein the non-steroidal anti-inflammatory drug (NSAID) is selected from the group consisting of aspirin, salicylate, φ naproxen, diclofen Acid (diclofenac), indomethacin, sulindac, ibuprofen' ketoprofen, oxaprozin, ketorolac ), sulindac, nabumetone 'meclofenamic, piroxicam, diflunisal, oxyphenbutazone ), phenylbutazone, celecoxib, rofecoxib, a COX2 inhibitor, acetaminophen, or a mixture or combination thereof.