Abstract:
Parenteral preparations of phospholipid-associated anti-inflammatories (PL-AIs) are described to treat pain/inflammation, with reduced gastrointestinal (GI) toxicity. The PL-AIs can be composed of phosphatidylcholine (“PC”) associated with non-steroidal anti-inflammatory drugs (“NSAIDs”). To prepare the PL-AIs, a phospholipid is mixed with an NSAID in a polar solvent, solvent is removed, suspended in an aqueous medium and sterilized by filtration or other acceptable method. Alternatively, the phospholipid can be mixed with an injectable preparation of an NSAID. The PL-AIs, and particularly PC associated with the NSAIDs, indomethacin, ibuprofen or diclofenac are useful for treating Patent Ductus Arteriosus in low birth weight infants to reduce the incidence of GI injury that may be manifest as Necrotizing Enterocolitis (NEC) or Spontaneous Intestinal Perforation (SIP). Other applications of the parenteral PL-AIs include prevention of: retinopathy of prematurity; and of pain from conditions associated with surgery, trauma, Sickle Cell Anemia and neural inflammation/injury.

Description:
[0001]     The present invention is a continuation-in-part of U.S. patent application Ser. No. 10/909,748, filed Aug. 2, 2004, which claims priority to U.S. Provisional Patent Application 60/491,568, filed Jul. 31, 2003. The entire contents of both application Ser. No. 10/909,748 and Provisional Patent Application No. 60/491,568 are hereby incorporated by reference. In addition, this application claims priority to U.S. Provisional Patent Application No. 60/833,388, filed Jul. 26, 2006, the entire content of which is hereby incorporated by reference. 
     
    
     BACKGROUND  
       [0002]     This invention relates to parenteral preparations of phospholipids and anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs (“NSAIDs”) or cyclooxygenase-2 (“COX-2”) inhibitors, and their methods of preparation and use. In particular, this invention relates to phospholipid-associated anti-inflammatories that are useful for treating or preventing traumatic shock, post-operative pain, sickle cell pain, chronic neuropathic pain, such as from spinal cord injury, and developmental conditions in low birth weight infants such as patent ductus arteriosus (“PDA”) and retinopathy, with reduced gastrointestinal (“GI”) injury.  
         [0003]     NSAIDs are effective pain-relievers and anti-inflammatory agents that can be taken by mouth. However, in unconscious/unresponsive patients or in low birth weight neonates, oral dosing may not be possible and drugs must be injected parenterally. NSAIDs that are associated with phospholipids, such as phosphatidylcholine (“PC-NSAIDs”) are new drugs that have fewer gastrointestinal side effects than regular NSAIDs and are safer for the patient when given chronically. Intravenously or intramuscularly administered NSAIDs can be used in the treatment of post-operative pain, but they create the risk of inducing GI ulceration and bleeding after surgery, and other concurrent damage to the GI membranes or layers. (Attridge et al.; Gabriel et al.; Wallace; Wolfe et al.). Because of solubility limitations, there are only a few NSAIDs that are approved for injections, and none of them are complexed to PC. In addition to post-operative pain, acute pain from vaso-occlusion due to sickle cell anemia may require hospitalization and parenteral pain management. Intravenous NSAID in the form of ketorolac has shown effective pain relief in many patients (Beiter et al.), but its chronic use is limited due to GI toxicity.  
         [0004]     Additionally, as many as 20% of low birth weight infants suffer from Patent Ductus Arteriosus (“PDA”), or insufficient closure of the ductus arteriosus, resulting in blood of the neonate bypassing the lungs and causing inadequate oxygenation. Closure of the ductus arteriosus in full-term infants occurs normally and with no complications. However, in premature infants this closure may not occur and can lead to serious developmental complications. The recommended treatment to promote closure of the duct is to administer intravenous indomethacin to inhibit prostaglandin synthesis in the vascular wall triggering the ductus closure. This treatment is not without risk as it has been reported that there is an association between the intravenous administration of indomethacin and other NSAIDs, and the development of another life-threatening condition called Spontaneous Intestinal Perforation (“SIP”) which may be a form of a related disease entity called Necrotizing Enterocolitis (“NEC”), both of which have a 20% mortality rate (Attridge). Premature infants are also at risk for retinopathy due to retinal angiogenesis caused by hyperoxygenation in incubators. It may be possible to prevent this retinopathy of prematurity by parenterally-administered ibuprofen which was reported to be effective in a murine model (Sharma).  
         [0005]     A method to make PC-NSAIDs that are sterile and can be administered intravenously, intramuscularly, or by other parenteral routes with reduced risk of GI damage would be useful for all patients and particularly to mitigate post-operative and sickle cell pain, chronic neuropathic pain, and for low birth weight neonates suffering from insufficient closure of the ductus arteriosus and/or retinopathy.  
       SUMMARY  
       [0006]     The present invention pertains to parenteral preparations of phospholipid-associated anti-inflammatory drugs and their methods of preparation and use. In particular, the present invention pertains to parenteral preparations containing complexes of phospholipids and anti-inflammatory drugs such as NSAIDs or COX-2 inhibitors. Administration of the parenteral preparations is useful for the treatment and prevention of traumatic shock, post-operative pain, sickle cell pain, neuropathic pain, and the treatment of low birth weight infants suffering from Patent Ductus Arteriosus (“PDA”) or retinopathy.  
         [0007]     One aspect of the invention relates to a composition comprising a parenteral phospholipid and an anti-inflammatory pharmaceutical such as NSAIDs, COX-2 inhibitors or the like.  
         [0008]     Another aspect of the invention is a method for making the parenteral preparations including the steps of contacting a phospholipid and an anti-inflammatory pharmaceutical in a heated polar solvent, removing the solvent, resuspending the anti-inflammatory-PC complex, and passing the composition through a membrane filter to produce a filter sterilized phospholipid-anti-inflammatory pharmaceutical preparation. An alternative method in preparing the sterile PC-associated anti-inflammatory for parenteral, oral, enteral or topical administration is to resuspend an injectable anti-inflammatory preparation, some of which may be commercially available, in a container containing PC as a dried powder or oil, followed by sonication or other means of agitation, and sterile filtration. Other means of sterilization include gamma irradiation, heat, chemical exposure, gas exposure, or a combination thereof.  
         [0009]     A further aspect of the invention is a method for administering sterilized phospholipid-anti-inflammatory pharmaceutical compositions including the steps of orally administering, topically administering, intradermally administering, subcutaneously administering, intramuscularly administering, intravenously administering, intra-arterially administering or directly administering into a tissue site an effective amount of the composition, where the administration can be a single administration, a periodic administration, a intermittent administration, or administration according to any administration protocol.  
         [0010]     An additional aspect of the invention is a method of treating or preventing Patent Ductus Arteriosus (“PDA”) and retinopathy in infants, and other uses of anti-inflammatory drugs in infants, by administering the compositions of this invention to the human or animal body by the above routes of administration or directly to the site of interest.  
         [0011]     Background information pertaining to phospholipids and anti-inflammatory pharmaceuticals may be found in U.S. Pat. Nos. 4,918,063, 5,043,329, 4,950,656, 5,032,585, 5,763,422, and 5,955,451; U.S. Provisional Patent Application No. 60/256,711; U.S. patent application Ser. No. 08/440,417; as well as International Patent Application Nos. PCT/US01/51605, PCT/US04/24807, and PCT/US05/36519, all of which are incorporated herein by reference.  
         [0012]     A further aspect of the invention is a method of reducing the GI toxicity of anti-inflammatory drugs, and particularly NSAIDs, when administered by all routes of administration, to treat or prevent traumatic shock or post-operative pain, to treat or prevent sickle cell pain, to treat or prevent neuropathic pain, such as chronic spinal cord injury pain, to treat or prevent PDA and retinopathy of prematurity, and to reduce the incidence of GI injury, ulceration, bleeding, Spontaneous Intestinal Perforation (“SIP”), or Necrotizing Enterocolitis (“NEC”) in a subject or patient, such as a low birth weight infant. The anti-inflammatory drugs that can be used in conjunction with phospholipids pursuant to the current invention include, but are not limited to, those listed in Table 1 below.  
                       TABLE 1                       CHEMICAL               CATEGORY   GENERIC NAME   TRADE NAME                   Propionic acids   Fenoprofen calcium   Nalfon ®           Flurbiprofen   Ansaid ®           Suprofen           Benoxaprofen           Ibuprofen (prescription)   Motrin ®           Ibuprofen (200 mg OTC)   Nuprin ®, Motrin IB ®           Ketoprofen   Orduis ®, Oruvall ®           Naproxen   Naprosyn ®           Naproxen sodium   Aleve ®, Anaprox ®,               Aflaxen ®           Oxaprozin   Daypro ®       Acetic acids   Diclofenac sodium   Voltaren ®           Diclofenac potassium   Cataflam ®           Etodolac   Lodine ®           Indomethacin   Indocin ®           Ketorolac tromethamine   Acular ®, Toradol ®           (intramuscular)           Ketorolac (oral)   Toradol ®       Ketones   Nabumetone   Relafen ®           Sulindac   Clinoril ®           Tolmetin sodium   Tolectin ®       Fenamates   Meclofenamate sodium   Meclomen ®           Mefenamic acid   Ponstel ®       Oxicams   Piroxicam   Feldene ®           Meloxicam   Mobic ®       Salicylic acid   Diflunisal   Dolobid ®           Aspirin           Salsalate   Disalcid ®       Pyrazolin acid   Oxyphenbutazone   Tandearil ®           Phenylbutazone   Butazolidin ®       COX-2 inhibitor   Celecoxib   Celebrex ®           Rofecoxib   Vioxx ®           Valdecoxib   Bextra ®           Etoricoxib   Arcoxia ®           Lumiracoxib   Prexige ®                  
 
     
    
     BRIEF DESCRIPTION OF FIGURES  
       [0013]      FIG. 1  shows a graph comparing the analgesic effects of intravenously administered indomethacin (“INDO”) and phosphatidylcholine (“PC”)-associated INDO (“INDO-PC”) in rats with Complete Freunds Adjuvant (CFA) joint inflammation. Indomethacin is given at 5 mg/kg;  
         [0014]      FIG. 2  shows a graph comparing the incidence of the side effect of intestinal bleeding after intravenous administration of INDO and INDO-PC in rats that had been treated with the NO-synthase inhibitor, L-NAME (at a dose of 20 mg/kg i.p.) 1 hr before, 1 and 4 hrs after NSAID administration. Indomethacin is given at 5 mg/kg;  
         [0015]      FIG. 3  shows a graph comparing the prostaglandin E 2  levels in inflamed tissue in rats with Complete Freunds Adjuvant (CFA) joint inflammation after intravenous administration of INDO and INDO-PC. Indomethacin is given at 5 mg/kg;  
         [0016]      FIG. 4  shows a graph comparing the blood level of INDO and INDO-PC in rats with Complete Freunds Adjuvant (CFA) joint inflammation after intravenous administration of the drugs. Indomethacin is given at 5 mg/kg;  
         [0017]      FIG. 5  shows a graph comparing the anti-inflammatory effects of subcutaneously administered INDO and INDO-PC in rats with Complete Freunds Adjuvant (CFA) joint inflammation. Indomethacin is given at 4 mg/kg;  
         [0018]      FIG. 6  shows a graph comparing the incidence of side effects of intestinal adhesions and perforations after subcutaneous administration of INDO and INDO-PC in rats with Complete Freunds Adjuvant (CFA) joint inflammation. Indomethacin is given at 4 mg/kg;  
         [0019]      FIG. 7  shows a graph comparing the prostaglandin E 2  levels in inflamed tissue in rats with Complete Freunds Adjuvant (CFA) joint inflammation after subcutaneous administration of INDO and INDO-PC. Indomethacin is given at 4 mg/kg;  
         [0020]      FIG. 8  shows a graph comparing the side effect of gastric bleeding 4 hrs after intravenous administration of ketorolac and ketorolac-PC in rats. Ketorolac is given at 15 mg/kg;  
         [0021]      FIG. 9  shows a graph comparing the side effect of intestinal bleeding 20 hrs after intravenous administration of diclofenac and diclofenac-PC in rats that had been treated with the NO-synthase inhibitor, L-NAME (at a dose of 20 mg/kg i.p.) 1 hr before, 1 and 4 hrs after NSAID administration. Diclofenac is given at 30 mg/kg.  
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0022]     This invention pertains to parenteral preparations of phospholipid-associated anti-inflammatory drugs, such as NSAIDs or COX-2 inhibitors. The PC-anti-inflammatory preparations are effective analgesics, anti-inflammatories, and anti-pyretics, as well as effective treatments for inducing the closure of the ductus arteriosus and preventing retinopathy in neonates, but with fewer gastrointestinal side effects. Although not wanting to be bound by any theory, our evidence that parenterally administered PL-associated NSAIDs have a reduced toxicity to the GI tract may be due to the unexpected likelihood that some or part of the PL remains attached to the NSAID during its secretion into the bile from the blood. In this way the NSAID that enters the GI lumen from the bile will have reduced toxicity to the GI mucosa due to it&#39;s association with PL.  
         [0023]     In a first preferred embodiment, a parenteral pharmaceutical preparation is prepared by contacting a phospholipid and an anti-inflammatory pharmaceutical in a polar solvent, preferably at an elevated temperature in the range of about 30° C. to about 60° C., cooling to room temperature if needed, removing the solvent by vacuum or by drying with an inert gas, resuspending the composition in an aqueous solution, and passing the composition through a membrane filter to produce a filter sterilized phospholipid-anti-inflammatory pharmaceutical preparation.  
         [0024]     Examples of preferred phospholipids include phosphatidylcholine (“PC”) and other zwitterionic phospholipids such as phosphatidylethanolamine, sphingomyelin and ceramides.  
         [0025]     Examples of preferred anti-inflammatory pharmaceuticals include NSAIDs and COX-2 inhibitors. In additional preferred embodiments, the anti-inflammatory pharmaceutical is indomethacin, aspirin, ibuprofen, diclofenac, etodolac, ketorolac, celecoxib and any of the NSAIDs listed previously in Table 1.  
         [0026]     Examples of preferred polar solvents include acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, methyl ethyl ketone, diethyl ether, and related solvents. The polar solvent is preferably utilized at an elevated temperature in the range of about 30° C. to about 60° C., and most preferably at about 40° C. The solvent is preferably removed through evaporation or drying.  
         [0027]     Examples of preferred aqueous solutions for resuspension include any suitable isotonic medium, such as sodium bicarbonate, saline, phosphate buffered saline, Ringer&#39;s lactate, dextrose, deoxycholate (at a weight/volume of about 0.05% to about 5%), and other IV solutions. Weight/volume as used herein is calculated by dividing the weight in grams of component A by 100 ml of a solution.  
         [0028]     The membrane filter through which the composition is passed to produce a sterile preparation is preferably one having a pore size in the range of about 0.22 μm to about 0.45 μm. Other methods of producing a sterile preparation include gamma irradiation, chemical exposure, gas treatment, heat, or a combination thereof.  
         [0029]     In a second preferred embodiment, the parenteral preparation is prepared by mixing an injectable anti-inflammatory pharmaceutical with a phospholipid in the absence of an organic solvent, generally accompanied by agitating the composition through sonication or some other method, and finally passing the composition through a membrane filter for sterilization. The injectable anti-inflammatory pharmaceutical can be any commercially available injectable product. Examples of commercially available injectable NSAID preparations include: indomethacin sold under the name Indocin-IV® (Ovation Pharmaceuticals, Deerfield, Ill.); ketorolac tromethamine sold under the name Toradol® (Roche Laboratories, Nutley, N.J.); diclofenac sodium sold under the name Votarol® (Novartis AG, Basel, Switzerland); and ibuprofen sold under the names NeoProfen® (Ovation Pharmaceuticals, Deerfield, Ill.) and Pedea® (Orphan Europe SARL, Paris, France). The phospholipid is preferably phosphatidylcholine in a dried powder or oil form.  
         [0030]     Prior to use as a pharmaceutical product, the parenteral preparations are preferably adjusted to a physiological pH in the range of about 6.5 to about 8.  
         [0031]     The sterile preparations can be administered through the steps of orally administering, topically administering, intradermally administering, subcutaneously administering, intramuscularly administering, intravenously administering, intra-arterially administering or directly administering into a tissue site an effective amount of the composition, where the administration can be a single administration, a periodic administration, a intermittent administration, or administration according to any suitable method of administration.  
         [0032]     The effective dosage, based on the body weight of the subject, of sterile preparation effective for the treatment can range from about 0.1 mg/kg to about 100 mg/kg, and preferably from about 1 mg/kg to about 20 mg/kg. The amount of PC in the sterile preparation can range from about 0.2 to about 400 mg/kg and preferably from about 2 mg/kg to about 40 mg/kg. The NSAID:PC weight ratio can range from 0.1:100 to 100:0.1 and is preferably from about 1:1 to about 1:3.  
         [0033]     In an additional preferred embodiment, the parenteral preparations are used to treat Patent Ductus Arteriosus (“PDA”) and prevent retinopathy in a subject such as a low birth weight infant. Preferable routes of administration for a subject are oral, enteral, or intravenous. Most preferred route of administration to an infant is intravenous administration. This treatment method has equivalent or enhanced therapeutic efficacy in inducing closure of the ductus arteriosus, with reduced toxicity to the GI tract. Treatment of infants having PDA with the sterile preparations rather than other anti-inflammatory compositions reduces the risk of the infant developing Spontaneous Intestinal Performations (“SIP”) or Necrotizing Enterocolitis (“NEC”).  
         [0034]     In a further preferred embodiment, the parenteral preparations are used to prevent, treat, or ameliorate inflammation, pain, or fever with fewer gastrointestinal side effects. In particular, the sterile preparations can be used to treat or prevent traumatic shock and post-operative pain, pain from sickle cell anemia, and neuropathic pain, such as chronic pain from spinal cord injury.  
         [0035]     While this invention has been described fully and completely, it should be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described. Although the invention has been disclosed with reference to its preferred embodiments, from reading this description those of skill in the art may appreciate changes and modification that may be made which do not depart from the scope and spirit of the invention as described above and claimed hereafter.  
       Example 1  
     Analgesic and Anti-Inflammatory Activity of Parenteral Preparations of Phospholipid-Associated Anti-Inflammatories  
       [0036]     Tests were performed to determine whether phosphatidylcholine (“PC”) complexed with an NSAID possessed equivalent activity and side effects compared to an NSAID alone, when administered intravenously.  
         [0037]     An NSAID in the form of indomethacin (3 grams) was placed into a glass vial and dissolved in acetone. Phosphatidylcholine (“PC”) (9 grams) was added to the vial and the combination was heated at 40° C. for 10 minutes, during which time both the NSAID and PC dissolved. The acetone solvent was evaporated under nitrogen gas and the remaining indomethacin-PC was resuspended in 1.25% sodium bicarbonate by sonication in a bath sonicator. The pH of the suspension was adjusted to pH 7.4 and the lipid mixture was forced through a 0.22 μm membrane filter to sterilize it.  
         [0038]     To test for analgesic activity, indomethacin (“INDO”) and INDO-PC were administered intravenously to rats with a chemically-induced Complete Freunds Adjuvant (“CFA”) paw inflammation, caused by the subcutaneous injection of 0.1 ml of CFA into the dorsal surface of the left hindpaw of a rat 4 days before. Saline was used as a control solution. Analgesia was assessed from the pain threshold which was measured by determination of the pressure which could be exerted on the inflamed paw before retraction by the animal, 30 minutes after IV administration of the test compounds. The results are shown in  FIG. 1 . Both INDO and INDO-PC at a dose of 5 mg/kg demonstrated equivalent levels of analgesia as seen by an increased pain threshold.  
         [0039]     For determination of NSAID&#39;s side effects, rats were injected intraperitoneally with the nitric oxide (“NO”) synthetase inhibitor N-nitroso-L-arginine methyl ester (“L-NAME”) at a dose of 20 mg/kg, at 1 hr before and 1 and 3 hrs after being dosed with the tested NSAIDs, to increase their sensitivity to the GI toxic actions of the drugs. The rats were administered a dose of 10 mg/kg of intravenous INDO or INDO-PC and one day later, flushes of the small intestine were analyzed for the presence of hemoglobin as an indication of GI bleeding.  FIG. 2  shows that INDO-PC induced significantly less GI bleeding than INDO alone.  
         [0040]     Another measure of drug activity was assessed by analysis of prostaglandin E 2  levels in inflamed tissue, which is typically lowered by indomethacin. In the same rats as shown in  FIG. 1 , PGE 2  was measured in the inflamed paws 30 minutes after IV administration of the test compounds. It is seen in  FIG. 3  that both INDO and INDO-PC reduced PGE 2  levels of the synovial fluid of the inflamed joints in a significant and equivalent manner.  
         [0041]     To determine if there was a difference in blood levels of the drugs, the same rats as shown in  FIGS. 1 and 3  were bled at 30 minutes after drug administration, and the blood was analyzed for INDO content by high-pressure liquid chromatography (“HPLC”).  FIG. 4  shows that both INDO and INDO-PC had measurable blood levels of INDO and there was no difference between INDO and INDO-PC groups.  
         [0042]     To test for anti-inflammatory activity after chronic drug administration, INDO and INDO-PC were administered subcutaneously for 4 days at 4 mg/kg to rats with a CFA induced paw inflammation. Inflammation was assessed by measurement of the thickness of the inflamed paw. The results in  FIG. 5  show that both INDO and INDO-PC significantly reduced paw swelling.  
         [0043]     To assess GI side effects in the animals in  FIG. 5 , measurements were made of the number of small intestinal adhesions and perforations.  FIG. 6  shows that INDO-PC gave significantly fewer intestinal adhesions and perforations than INDO.  
         [0044]     To assess anti-inflammatory activity by another means in chronically dosed animals, PGE 2  levels in paw synovial fluid of rats in  FIG. 5  was measured. The results in  FIG. 7  show that both INDO and INDO-PC significantly reduced inflammation-induced PGE 2  and in to a similar extent.  
       Example 2  
     Reduced GI Side Effects of Other PC-NSAID Compounds  
       [0045]     To show that other PC-NSAIDs exhibit reduced GI side effects, formulations of ketorolac-PC (1:2 (wt.:wt.)) and diclofenac-PC (1:2 (wt.:wt.)) were prepared. Rats were administered 15 mg/kg of intravenous ketorolac or ketorolac-PC, and 4 hours later flushes of the stomach were analyzed for the presence of hemoglobin as an indication of GI bleeding.  FIG. 8  shows that ketorolac-PC induced significantly less bleeding than ketorolac alone. Other rats were administered 30 mg/kg of intravenous diclofenac or diclofenac-PC in the L-NAME model described above. Flushes of the small intestine were analyzed for the presence of hemoglobin as an indication of GI bleeding.  FIG. 9  shows that diclofenac-PC induced significantly less GI bleeding than diclofenac alone.  
       Example 3  
     Analgesic Effects of Ibuprofen-PC in Chronic Neuropathic Pain  
       [0046]     To show that ibuprofen-PC is effective at relieving the chronic neuropathic pain from spinal cord injury, rats are subjected to a controlled spinal injury and tested 6 weeks later after development of chronic pain. The injury consists of spinal T10 level impaction under anesthesia with an Infinite Horizon Impactor using 150 kDyne force for 1 second dwell time. After recovery for 6 weeks, animals are tested to confirm the presence of chronic pain by the Randall-Selitto test which consists of quantifying the withdrawal response to mechanical force applied to the hindpaw. Then ibuprofen or ibuprofen-PC at 1-100 mg/kg, iv, are administered and the rats tested again for pain 2 hours later.  
         [0047]     Overall, these studies show that PC-NSAID formulations can be sterilized for intravenous, intra-arterial or direct administration into veins, arteries or tissues. The PC-NSAID formulation is equivalent in biological activity and blood level to the NSAID alone, but has less GI bleeding as a side effect, making it a safer drug.  
       REFERENCES CITED  
       [0048]     The following U.S. Patent documents and publications are hereby incorporated by reference.  
       U.S. Patents  
       [0049]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                   
               
               
                   
                 U.S. Pat. No. 
                 Issued to: 
               
               
                   
                   
               
             
             
               
                   
                 4,918,063 
                 Lichtenberger 
               
               
                   
                 5,043,329 
                 Lichtenberger 
               
               
                   
                 4,950,656 
                 Lichtenberger 
               
               
                   
                 5,032,585 
                 Lichtenberger 
               
               
                   
                 5,763,422 
                 Lichtenberger et al. 
               
               
                   
                 5,955,451 
                 Lichtenberger et al. 
               
               
                   
                   
               
             
          
         
       
     
       U.S. Patent Applications  
       [0050]     Provisional Application Ser. No. 60/256,711  
         [0051]     application Ser. No. 08/440,417 
                                             Foreign Patent Documents                                    PCT/US01/51605   Lichtenberger           PCT/US04/24807   Lichtenberger           PCT/US05/36519   Lichtenberger                      
 
       Other Publications  
       [0000]    
       
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          Beiter, J. L., Simon, H. K., Chambliss, C. R., Adamkiewicz, T., Sullivan, K. Intravenous ketorolac in the emergency department management of sickle cell pain and predictors of its effectiveness. Arch. Pediatr. Adolesc. Med. 2001; 155:496-500.  
          Lichtenberger L M, Wang Z-M, Romero J J, Ulloa C, Perez J C, Giraud M-N, Barreto J C (1995). Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: Insight into the mechanism and reversal of NSAID-induced gastrointestinal injury.  Nature Med  1: 154-158.  
          Gabriel, S. E., Jaakkimainen, L, and Bombardier, C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: A meta-analysis.  Ann Intern Med,  1991; vol. 115: 787-96.  
          Sharma, J., Barr, S. M., Geng, Y., Yun, Y., Higgins, R. D. Ibuprofen improves oxygen-induced retinopathy in a mouse model. Current Eye Research 2003; 27: 309-314.  
          Wallace, J. L. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years.  Gastroenterology  1997; vol. 112: 1000-1016.  
          Wolfe, P. A., Polhamus, C. D., Kubik, C., Robinson, A. B., Clement, D. J. Giant duodenal ulcers associated with postoperative use of ketorolac: report and three cases.  Am. J. Gastroenterology  1994; vol. 89: 1110-1111.