Patent Application
20080051373
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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's association with PL.
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.
Examples of preferred phospholipids include phosphatidylcholine (“PC”) and other zwitterionic phospholipids such as phosphatidylethanolamine, sphingomyelin and ceramides.
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.
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.
Examples of preferred aqueous solutions for resuspension include any suitable isotonic medium, such as sodium bicarbonate, saline, phosphate buffered saline, Ringer'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.
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.
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.
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.
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.
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.
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”).
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.
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.
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.
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.
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
For determination of NSAID'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.
Another measure of drug activity was assessed by analysis of prostaglandin E2 levels in inflamed tissue, which is typically lowered by indomethacin. In the same rats as shown in
To determine if there was a difference in blood levels of the drugs, the same rats as shown in
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
To assess GI side effects in the animals in
To assess anti-inflammatory activity by another means in chronically dosed animals, PGE2 levels in paw synovial fluid of rats in
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.
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.
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.
The following U.S. Patent documents and publications are hereby incorporated by reference.
Provisional Application Ser. No. 60/256,711
application Ser. No. 08/440,417
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.
| Number | Date | Country | |
|---|---|---|---|
| 60491568 | Jul 2003 | US | |
| 60833388 | Jul 2006 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10909748 | Aug 2004 | US |
| Child | 11881058 | Jul 2007 | US |
