US 20080317805A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0317805 A1 McKay et al. (43) Pub. Date: Dec. 25, 2008

(54) LOCALLY ADMINISTRATED LOW DOSES Publication Classification OF CORTICOSTEROIDS (51) Int. Cl. A6II 3/566 (2006.01) (76) Inventors: William F. McKay, Memphis, TN A6II 3/56 (2006.01) (US); John Myers Zanella, A6IR 9/00 (2006.01) Cordova, TN (US); Christopher M. A6IP 25/04 (2006.01) Hobot, Tonka Bay, MN (US) (52) U.S. Cl...... 424/422:514/169; 514/179; 514/180 (57) ABSTRACT Correspondence Address: This invention provides for using a locally delivered low dose Medtronic Spinal and Biologics of a corticosteroid to treat pain caused by any inflammatory Attn: Noreen Johnson - IP Legal Department disease including sciatica, herniated disc, Stenosis, mylopa 2600 Sofamor Danek Drive thy, low back pain, facet pain, osteoarthritis, rheumatoid Memphis, TN38132 (US) arthritis, osteolysis, tendonitis, carpal tunnel syndrome, or tarsal tunnel syndrome. More specifically, a locally delivered low dose of a corticosteroid can be released into the epidural (21) Appl. No.: 11/765,040 space, perineural space, or the foramenal space at or near the site of a patient's pain by a drug pump or a biodegradable drug (22) Filed: Jun. 19, 2007 depot.

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LOCALLY ADMINISTRATED LOW DOSES gesia refers to the perception of pain directly from the imme OF CORTICOSTEROIDS diately damaged tissues. Secondary hyperalgesia refers to the perception of extreme pain sensitivity emanating from tissues CROSS-REFERENCE TO RELATED immediately Surrounding the primary tissue injury. Hence APPLICATIONS secondary hyperalgesia involves situations where the increased sensitization to pain has extended beyond the FIELD OF THE INVENTION immediate injury and to the Surrounding apparently undam 0001. This invention provides for using a locally delivered aged adjacent tissues. Inflammatory mediators involved in low dose of a corticosteroid to treat pain caused by any pain are allied with various disorders that may include with inflammatory disease including Sciatica, herniated disc, out limitation: osteoarthritis, rheumatoid arthritis, osteolysis, Stenosis, mylopathy, low back pain, facet pain, osteoarthritis, tendonitis, Sciatica, herniated disc, Stenosis, mylopathy, low rheumatoid arthritis, osteolysis, tendonitis, carpal tunnel Syn back pain, facet pain, tendonitis, carpal tunnel syndrome, drome, or tarsal tunnel syndrome. More specifically, a locally tarsal tunnel syndrome, mylopathy, etc. delivered low dose of a corticosteroid can be released into the 0007. In general, inflammation is a normal and essential epidural space, perineural space, or the foramenal space at or response to any noxious stimulus and may vary from a local near the site of a patient's pain by a drug pump or a biode ized to a generalized response. The inflammatory response gradable drug depot. generally follows a sequence of events that include, 1) an initial injury causing release of inflammatory mediators. Such BACKGROUND OF THE INVENTION as, histamine, serotonin, leukokinins, SRS-A, lysosomal enzymes, lymphokinins, prostaglandins, etc.; 2) vasodilation, 0002 Pain is associated with many medical conditions including increased vascular permeability and exudation; 3) and affects millions of Americans. The American Pain Foun leukocyte migration, chemotaxis, and phagocytosis; and 4) dation reports that over 50 million Americans suffer from proliferation of connective tissue cells. chronic pain including 20% of individuals aged 60 and over 0008 Corticosteroids are known in the art as being useful who are affected by joint (arthritis or other disorders) and for treating inflammation. Corticosteroids influence all tis back pain. Furthermore, nearly 25 million Americans expe sues of the body and produce various cellular effects. These rience acute pain due to injuries or Surgical procedures each steroids regulate carbohydrate, lipid, proteinbiosynthesis and year. The cost involved in the management of pain has been metabolism, and water and electrolyte balance. Corticoster estimated at S100 billion each year. In addition to its eco oids influencing cellular biosynthesis or metabolism are nomical burden, pain has a tremendous effect on the quality of referred to as glucocorticoids while those affecting water and life of affected individuals and is one of the most common electrolyte balance are mineralocorticoids. Both glucocorti causes of acute and chronic disabilities. coids and mineralocorticoids are released from the cortex of 0003. The human body perceives pain when body tissues, the adrenal gland. Cortisol is the most potent glucocorticoid including nerve fibers, are damaged by pathogens, trauma, secreted from the adrenal gland. inflammatory conditions or noxious stimuli ranging from 0009 For the treatment of sciatica corticosteriods have harmful or noxious mechanical stimuli, hot and/or cold been injected into the lumbar epidural space. These steroids stimuli, or chemical stimuli. Mast cells associated with dam regulate inflammation by reducing vasodilation and the abil aged tissue and nerve fibers initiate the inflammation process ity of phagocytes to permeate tissues. The current gold stan by secreting inflammatory mediators, e.g. Tumor Necrosis dard non-Surgical treatment of Sciatica is a steroid laced epi Factor-alpha (TNF-a), histamine, Interleukin-1 (IL-1). IL-6, dural injection. The clinical benefit of these injections is a IL-8, and nerve growth factors (NGF). matter of controversy. There are no set guidelines for this 0004. These mediators cause other cells, such as mono procedure and complications have been associated with large cytes, neutrophiles, and similar cells, to migrate to the trauma bolus steroid injections used to curtail neurological pain. site. Further, these mediators also help some of the white (0010 U.S. Pat. No. 6,468.527 (the 527 Patent) discloses a cells, such as phagocytes, to activate their own inflammatory bio-based sealant composition and methods of preparation mediators. Inflammatory mediators, such as, NGFs secreted and use. The bio sealant disclosed in the 527 Patent includes by damaged or irritated nerve cells and fibers have been combining fibrinogen and thrombin, and a corticosteroid, shown to increase the number of active nerve fibers, particu where the corticosteroid is used to reconstitute the thrombin larly sensory fibers A and C that are involved in the transmis from a freeze-dried state. The steroid is delivered to and held sion of nociceptive modalities. Ad fibers, a subset of the A at the target area by fibrinogen's natural conversion to a fibrin fibers, primarily carry the fast pain, that is, the abrupt and clot. sharp sensation type of pain quality. The C fibers are primarily O011 U.S. Pat. No. 5,336,505 (the 505 Patent) discloses responsible for transmission of the slow burning type of pain bioerodible ortho ester polymers suitable for preparing bio quality. erodible pharmaceutical compositions such as implants, oint 0005 Pain and the extent of the area affected by pain can often be defined by the measure of allodynia and hyperalge ments, creams, gels, and the like. The 505 Patent discloses sia. Allodynia is a painful response to an otherwise non the use of specific polyorthoesters to deliver a corticosteroid. noxious stimuli. In other words, allodynia refers to pain resulting from a stimulus that ordinarily does not elicit a SUMMARY OF THE INVENTION painful response, such as, light pressure, the movement of 0012. The present invention overcomes the drawbacks of clothes over the skin, or the application of mild heat or cold. prior art by providing a locally delivered low dose of a corti 0006 Hyperalgesia is an extreme sensitivity to pain. That costeroid to treat pain caused by any inflammatory disease is, a mild noxious stimulus may be perceived as an extremely including sciatica, herniated disc, Stenosis, mylopathy, low painful stimulus. In addition, hyperalgesia usually consists of back pain, facet pain, osteoarthritis, rheumatoid arthritis, primary and secondary hyperalgesic areas. Primary hyperal osteolysis, tendonitis, carpal tunnel syndrome, or tarsal tun US 2008/031 7805 A1 Dec. 25, 2008 nel syndrome. More specifically, a locally delivered low dose nisolone acetate, methylprednisolone sodium Succinate, of a corticosteroid can be released into the epidural space, prednisolone, prednisolone acetate, prednisolone sodium perineural space, or the foramenal space at or near the site of phosphate, prednisolone tebutate, clocortolone pivalate, fluo a patient's pain by a drug pump or a biodegradable drug depot. cinolone, dexamethasone 21-acetate, betamethasone 17-val 0013. It is an object of the invention, wherein a biodegrad erate, isoflupredone, 9-fluorocortisone, 6-hydroxydexam able drug depot comprises an implant made from a natural or ethasone, dichlorisone, meclorisone, flupredidene, synthetic biocompatible biodegradable material. Natural doxibetasol, halopredone, halometaSone, clobetaSone, diflu polymers include, but are not limited to, proteins such as cortolone, isoflupredone acetate, fluorohydroxyandrostene albumin, collagen, gelatin, synthetic poly(aminoacids), and dione, beclomethasone, flumethasone, diflorasone, fluocino prolamines; glycosaminoglycans, such as hyaluronic acid lone, clobetasol, cortisone, paramethasone, clocortolone, and heparin; polysaccharides. Such as alginates, chitosan, prednisolone 21-hemisuccinate free acid, prednisolone meta starch, and dextans; and other naturally occurring or chemi Sulphobenzoate, prednisolone terbutate, and triamcinolone cally modified biodegradable polymers. Synthetic biocom acetonide 21-palmitate. patible biodegradable materials includebut are not limited to, 0018. An object of the invention includes having a biode polyhydroxybutyric acid, poly(trimethylene carbonate), gradable drug depot, wherein the corticosteroid is fluocino polycaprolactone (PCL), polyvalerolactone, poly(alpha-hy lone and is released by the biocompatible biodegradable droxy acids), poly(lactones), poly(amino-acids), poly(anhy polymer at or near a site of a patient's pain at a rate not to drides), polyketals poly(arylates), poly(orthoesters), poly(or exceed about 10 g/kg/day. The rate of delivery can also range thocarbonates), poly(phosphoesters), poly(ester-co-amide), from about 1.6 ug/kg/day to about 2.56x10'ug/kg/day. poly(lactide-co-urethane, polyethylene glycol (PEG), poly vinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer 0019. An object of the invention includes having a biode (polyactive), methacrylates, poly(N-isopropylacrylamide), gradable drug depot, wherein the corticosteroid is dexam PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, ethasone and is released by the biocompatible biodegradable and PLGA-PEO-PLGA blends and copolymers thereof and polymer at or near a site of a patient's pain at a rate not to any combinations thereof. It is another object of the invention, exceed about 100 ug/kg/day. The rate of delivery can also wherein the biodegradable drug depot is made of an implant range from about 20.0 ug/kg/day to about 0.001 ug/kg/day. able biocompatible biodegradable polymer comprising com 0020. Yet another object of the invention includes having positions of micro-particles, micro-spheres, capsules, gels, a biodegradable drug depot, wherein a locally delivered low coatings, matrices, wafers, pills, pellets, or other pharmaceu dose of a corticosteroid is admixed with a biodegradable tically deliverable compositions and any combinations polymer for control release at or near the site of a patient's thereof. pain comprising loadings of said corticosteroid from about 0014. It is yet another object of the invention, wherein the 0.1% to about 99% (w/w) of the polymer, more preferably biodegradable drug depot is placed at or near the site of a about 1% to about 80%, more preferably about 1% to about patient's pain, which may include pain in any area within a 50%, most preferably about 1% to about 30%. human body resulting from inflammation, mechanical 0021. It is an object of the invention wherein the biode stimuli, chemical stimuli, thermal stimuli, or any combina gradable drug depot has a locally delivered low dose of a tion thereof. corticosteroid that is associated with micro-particles includ 0015. An embodiment of the invention includes having a ing in a suitable vehicle where said locally delivered low dose biodegradable drug depot, wherein the biocompatible biode of a corticosteroid is present in a weight percent relative to gradable polymer releases a low dose of a corticosteroid said micro-particle from about 0.1% to about 99% (w/w) of locally at or near the site of a patient's pain, which includes the polymer, more preferably about 1% to about 80%, more the epidural spaces, perineural spaces, or foramenal spaces preferably about 1% to about 50%, most preferably about 1% Surrounding an area of nerve irritation or the dorsal root to about 30%. It is an object of the invention, wherein the ganglia. biodegradable drug depot further comprises a pharmaceuti cally acceptable excipient. 0016. Another embodiment of the invention includes hav ing a biodegradable drug depot, wherein the biocompatible 0022. An embodiment of the invention includes having a biodegradable polymer is composed of micro-particles hav biodegradable drug depot for treating a patient's pain, ing a particle size of about 0.1 um to about 1000 um, more wherein the patient's pain is caused by an inflammatory dis preferably 1 um to 200 um, and is associated with a locally ease comprising Sciatica, herniated disc, Stenosis, mylopathy, delivered low dose of a corticosteroid. low back pain, facet pain, osteoarthritis, rheumatoid arthritis, 0017. Yet another embodiment of the invention includes osteolysis, tendonitis, carpal tunnel syndrome, or tarsal tun having a biodegradable drug depot, wherein the corticoster nel syndrome. oid comprises dexamethasone, betamethasone, triamcino 0023 Yet another embodiment of the invention provides lone, triamcinolone acetonide, triamcinolone diacetate, tri for a method of treating a patient's pain comprising the steps amcinolone hexacetonide, beclomethasone dipropionate, of i) selection of a pain site for the local delivery of a corti beclomethasone dipropionate monohydrate, flumethasone costeroid; ii) placement of a biodegradable drug depot at or pivalate, diflorasone diacetate, fluocinolone acetonide, fluo near the selected site and, iii) release of a locally delivered low rometholone, fluorometholone acetate, clobetasol propi dose of a corticosteroid at or near the selected site. onate, desoximethasone, fluoxymesterone, fluprednisolone, 0024. It is an object of the invention, wherein the method hydrocortisone, hydrocortisone acetate, hydrocortisone for treating a patient's pain includes pain caused by an inflam butyrate, hydrocortisone sodium phosphate, hydrocortisone matory disease comprising Sciatica, herniated disc, Stenosis, Sodium Succinate, hydrocortisone cypionate, hydrocortisone mylopathy, low back pain, facet pain, osteoarthritis, rheuma probutate, hydrocortisone Valerate, cortisone acetate, toid arthritis, osteolysis, tendonitis, carpal tunnel syndrome, paramethasone acetate, methylprednisolone, methylpred or tarsal tunnel syndrome. US 2008/031 7805 A1 Dec. 25, 2008

0025 Yet another embodiment of the invention includes a 0036 FIG. 2 illustrates the effect of various doses of dex method of treating a patient's pain, wherein delivery of the amethosonse and fluocinolone on mechanical allodynia biodegradable drug depot includes using a syringe and needle response in the rat CCI model. or canula to inject the depot at or near the site of a patient's pa1n. DETAILED DESCRIPTION OF THE INVENTION 0026. It is an object of the invention wherein the method of treating pain includes delivery of the biodegradable drug 0037. Definitions depot by placing an implant having a viscous, solid, or gel I0038 “Locally released low dose.” “locally delivered low form comprising micro-particles, micro-capsules, capsules, dose.” or “locally administrated low dose' all refer to the gels, coatings, matrices, wafers, pills, pellets, other pharma amount of corticosteroid delivered locally to relieve pain due ceutically delivery compositions, or combinations thereof at to inflammation, which that is less than a dose that would or near said site of a patient's pain. typically be given systemically to a patient suffering from 0027. It is an object of the invention, wherein the method Such pain. For example, locally released low doses of corti of treatingapatient's pain includes delivery of the biodegrad costeroids delivered daily in human may include without able drug depot at or near a site of a patient's pain by using an limitation: cortisone: 2.5 mg/day; prednisone: 0.5 mg/day; epidural needle/catheter or canula assembly or placement in methylprednisolone: 0.4 mg/day; triameinolone: 0.4 mg/day: the patient during surgery. betamethasone: 7.5 g/day; dexamethasone: 7.5 g/day; 0028. Yet another object of the invention includes a hydrocortisone: 2.0 mg/day; fluocinolone 0.3 ug/day. Locally method for treating a patient's pain, wherein the site of a released low doses of corticosteroids should have a dose not patient's pain includes epidural spaces, perineureal spaces, to exceed 100 ug/kg/day, 90 g/kg/day, 80 g/kg/day, 70 foramenal spaces, or the dorsal root ganglia. g/kg/day, 60 Lig/kg/day, 50 g/kg/day, 40 g/kg/day, 30 0029. It is an object of the invention, wherein the method g/kg/day, 20 g/kg/day, and 10 g/kg/day (and every integer of treating a patient's pain includes the corticosteroid being between 100 and 10). either fluocinolone, dexamethasone or combinations thereof. 0039) “Biodegradable drug depot,” “drug depot,” “the 0030. It is an embodiment of the invention, wherein the depot,” or "depot” refer to any foreign implant that a physi method for treating a patient's pain is the administration of a cian places into a body to release a locally delivered low dose corticosteroid being administered at a rate not to exceed 100 of a corticosteroid to a patient's site of pain. The foreign g/kg/day. The rate can also range from about 100 g/kg/day implant may include without limitation: micro-particles, to about 1 pg/kg/day depending upon the specific activity of micro-spheres, capsules, gels, coatings, matrices, wafers, the compound. More specifically the corticosteroid being pills, fibers, pellets, or other appropriate pharmaceutical administered at a rate of about 50 g/kg/day to about 100 delivery compositions; all of which may, or may not, be made pg/kg/day. Most specifically the corticosteroid being admin from a biodegradable polymer. The biodegradable polymers istered at a rate of about 30 ug/kg/day to about 500 pg/kg/day. degrade into non-toxic residues that the body easily removes 0031. It is an object of the invention, wherein the method or break down or dissolve slowly and are cleared from the of treating a patient's pain includes having a drug pump body intact. The polymers may be cured in-vivo or, in the deliver a composition comprising a locally released low dose alternative, ex-Vivo, forming a solid matrix that incorporates of a corticosteroid at or near a site of a patient's pain. the drug for controlled release to an inflammatory region. 0032. Yet another embodiment of the invention includes a Suitable biodegradable polymers may include, without limi method for treating a patient’s pain, wherein the locally tation natural or synthetic biocompatible biodegradable released low dose of a corticosteroid is delivered by a drug material. Natural polymers include, but are not limited to, pump and the composition comprising a locally released low proteins such as albumin, collagen, gelatin synthetic poly dose of a corticosteroid includes either fluocinolone, dexam (aminoacids), and prolamines; glycosaminoglycans, such as athasone, or combinations thereof. hyaluronic acid and heparin; polysaccharides, such as algi 0033. Another embodiment of the invention includes a nates, chitosan, starch, and dextans; and other naturally method for treating a patient's pain, wherein said drug pump occurring or chemically modified biodegradable polymers. administers locally released low dose of a corticosteroid at a Synthetic biocompatible biodegradable materials include, rate not to exceed 100 ug/kg/day. The rate may range from but are not limited to, poly(lactide-co-glycolide) (PLGA), about 100 g/kg/day to about 1 pg/kg/day depending upon the polylactide (PLA), polyglycolide (PG), polyhydroxybutyric specific activity of the compoundator near a site of a patient's acid, poly(trimethylene carbonate), polycaprolactone (PCL), pain. More specifically the corticosteroid being administered polyvalerolactone, poly(alpha-hydroxy acids), poly(lac at a rate of about 50 g/kg/day to about 100 pg/kg/day. Most tones), poly(amino-acids), poly(anhydrides), polyketals poly specifically the corticosteroid being administered at a rate of (arylates), poly(orthoesters), poly(orthocarbonates), poly about 30 g/kg/day to about 500 pg/kg/day. (phosphoesters), poly(ester-co-amide), poly(lactide-co 0034. Yet another embodiment of the invention includes urethane, polyethylene glycol (PEG), polyvinyl alcohol having a method for treating a patient's pain, wherein the (PVA). PVA-g-PLGA, PEGT-PBT copolymer (polyactive), patient's pain is caused by an inflammatory disease compris methacrylates, poly(N-isopropylacrylamide). PEO-PPO ing sciatica, herniated disc, Stenosis, mylopathy, low back PEO (pluronics), PEO-PPO-PAA copolymers, and PLGA pain, facet pain, osteoarthritis, rheumatoid arthritis, osteoly PEO-PLGA blends and copolymers thereof and any combi sis, tendonitis, carpal tunnel syndrome, or tarsal tunnel syn nations thereof. drome. 10040) "Patient” refers to any animal, preferably a mam mal, wherein mammal may include but is not limited to a dog, BRIEF DESCRIPTION OF THE DRAWINGS cat, cattle, horse, sheep, ram, llama, monkey, ape, or human. 0035 FIG. 1 illustrates the effect of various doses of dex 0041) "Drug pump' refers to any device that may be amethosone and fluocinolone on thermal paw withdrawal placed into the body by a physician or veterinarian, or alter latency in the rat CCI model. natively, on the outside of the body that releases a locally US 2008/031 7805 A1 Dec. 25, 2008

delivered low dose of a corticosteroid by a mechanical or causing inflammatory pain or is within about 0.1 cm to about electromechanical pumping action to a inflammatory site 10 cm from said damaged tissues or nerve cells or fibers, within the body via an implanted catheter. preferably less than 5 cm from the injury or inflammatory site. 0042 “Neurogenic inflammation” refers to inflammation 0050. Descriptions of various embodiments of the inven caused by the local release of inflammation mediators by tion are given below. Although these embodiments are pri inflammatory related cells associated with irritated or dam marily intended to treat pain associated with neurogenic aged nerve cells or fibers and the like within the human body. inflammation in or about the epidural or perinural spaces of 0043 “Delivery” refers to any means used to place the the body, it should not be inferred that the invention is only for drug into a patient. Such means may include without limita these uses. Any and all uses of specific words and references tion, placing into a patient a biodegradable drug depot that are simply to detail different embodiments of the present releases the drug into a target area or attaching or inserting a invention. drug pump in a patient that releases the drug into a target area 0051. Also, any and all alterations and further modifica or inserting a drug pump in to a patient that releases the drug tions of the invention, as would occur to one of ordinary skill into a target area. One of ordinary skill in the art recognizes in the art, are intended to be within the scope of the invention. that the biodegradable drug depot may be delivered by a wide A non-limiting example is the prevention of osteo-diseases variety of methods, e.g. placement into a drill site, injection brought on by inflammation. by a syringe, catheter orcanula assembly, or forceful injection 0.052 Selection of Corticosteroids and Drug Dosage by a gun type apparatus, or by placement into a Surgical site in 0053 Corticosteroids associated with the present inven a patient during Surgery. Further, various pumping machines tion can be any naturally occurring or a synthetic steroid may also deliver drugs into a target area, e.g. an osmotic hormone. Naturally occurring corticosteroids are secreted by pump, an interbody pump, infusion pump, implantable mini the adrenal cortex or generally the human body. Corticoste pumps, a peristaltic pump, other pharmaceutical pumps, or a riods may have glucocorticoid and/or mineralocorticord system administered locally by insertion of a catheter at or activity. For the present invention non-limiting examples of near a target site with the catheter being operably connected corticosteroids may include: dexamethasone, betametha to a pharmaceutical delivery pump. Sone, triamcinolone, triamcinolone acetonide, triamcinolone 0044) The terms “treatment' and “treating a patient refer diacetate, triamcinolone hexacetonide, beclomethasone to reducing, alleviating, stopping, blocking, or preventing the dipropionate, beclomethasone dipropionate monohydrate, symptoms of pain in a patient. For the inventions described flumethasone pivalate, diflorasone diacetate, fluocinolone herein, “treatment” and “treating includes partial alleviation acetonide, fluorometholone, fluorometholone acetate, clobe of symptoms as well as complete alleviation of the symptoms tasol propionate, desoximethasone, fluoxymesterone, flu for a time period. The time period can be hours, days, months, prednisolone, hydrocortisone, hydrocortisone acetate, hydro or even years. cortisone butyrate, hydrocortisone sodium phosphate, 0045 “Site of a patient’s pain” refers to any area within a hydrocortisone sodium Succinate, hydrocortisone cypionate, body causing pain, e.g. nerve root causing Sciatic pain, nerve hydrocortisone probutate, hydrocortisone Valerate, cortisone fibers growing into annular tears in discs causing back pain, a acetate, paramethasone acetate, methylprednisolone, methyl knee joint with osteoarthritis, or pain radiating from epidural prednisolone acetate, methylprednisolone sodium Succinate, or perineural spaces. The pain perceived by the patient may prednisolone, prednisolone acetate, prednisolone sodium result from inflammatory responses, mechanical stimuli, phosphate, prednisolone tebutate, clocortolone pivalate, fluo chemical stimuli, thermal stimuli, as well as allodynia. cinolone, dexamethasone 21-acetate, betamethasone 17-val 0046 Alternatively, the site of a patient's pain may include erate, isoflupredone, 9-fluorocortisone, 6-hydroxydexam any place within the body where the biodegradable drug ethasone, dichlorisone, meclorisone, flupredidene, depot or the drug pump is used in the present invention, doxibetasol, halopredone, halometaSone, clobetaSone, diflu including but is not limited to any site of injury which is cortolone, isoflupredone acetate, fluorohydroxyandrostene causing or will cause inflammation, Such as a Surgical site. dione, beclomethasone, flumethasone, diflorasone, fluocino 0047. Additionally, the site of a patient's pain can com lone, clobetasol, cortisone, paramethasone, clocortolone, prise one or multiple sites in the spine, Such as between the prednisolone 21-hemisuccinate free acid, prednisolone meta cervical, thoracic, or lumbar vertebrae, or can comprise one Sulphobenzoate, prednisolone terbutate, and triamcinolone or multiple sites located within the immediate area of acetonide 21-palmitate. inflamed or injured joints such as the shoulder, hip, or other 0054 The invention includes using a locally released low joints. Implantation of the biodegradable drug depot or the dose of a corticosteroid delivered daily to treat pain. A locally drug pump can occur simultaneously with Surgery to repaira delivered low dose may include any daily amount of corti fracture, remove a tumor, etc., or can be performed in indi costeroid released by a pump or drug depot that may be less viduals who experience pain, especially chronic pain, as the than a systemic dose that would typically be given to a patient result of earlier trauma, injury, Surgery, or other initiator of Suffering from inflammatory pain. For example, locally deliv inflammation. ered low doses of corticosteroids delivered daily in human 0048. The site of a patient's pain also includes areas of may include without limitation: cortisol: 2.5 mg/day; pred perceived pain where the drug is deposited within a tissue, for nisone: 0.5 mg/day; methylprednisolone: 0.4 mg/day; tri example, a nerve root of the nervous system or a region of the ameinolone: 0.4 mg/day; betamethasone: 7.5 g/day; dexam brain, or in close proximity (within about 10 cm, or preferably ethasone: 7.5 g/day; hydrocortisone: 2.0 mg/day; within about 5 cm, for example) thereto. fluocinolone 0.3 ug/day. The dosage is not to exceed 100 0049. At or near or adjacent to the site of a patient's pain' ug/kg/day, 90 ug/kg/day, 80 g/kg/day, 70 g/kg/day, 60 refers to any place within the body where the biodegradable ug/kg/day, 50 lug/kg/day, 40 g/kg/day, 30 g/kg/day, 20 drug depot or the drug pump is used in the present invention ug/kg/day, and 10 g/kg/day (and every integer between 100 that is immediately adjacent to damaged tissue or nerve fibers and 10). US 2008/031 7805 A1 Dec. 25, 2008

0055. In certain embodiments, the dosage is provided by polymers may be used in making controlled release or Sus the biodegradable drug depot or delivered by various types of tained release compositions disclosed herein. drug pumps, however the drug is to be provided at a low dose 0061 Poly(d.1-lactic-co-glycolic acid) (PLGA) is com at or in close proximity to the target region of inflammation. mercially available from Alkermes of Cambridge, Mass. Suit It is desirable that the corticosteroids of the instant invention able Alkermes products include 00 DL 7E, 8515 DLG 7E, be carefully formulated for delivery in locally released low 7525 DLG 7E, 6535 DLG 7E, 5050 DLG 7E (Lakeshore doses for the desired modulation of inflammation in a con Biomaterials, Birmingham, Ala.); LactelTM, (Durect, Pelham, trolled and direct manner. Further, the biodegradable drug Ala.); and ResomerTM (Boeringer Ingelheim) and poly(d.1- depot or a drug pump may deliver a low dose corticosteroid lactic acid) (d.1-PLA), where the product’s mole percent com ranging in a continuum from a rapid or immediate release to position of lactide and glycolide are given. For example, 7525 a Sustained release. DLG 7E have the mole percentratios of 75% lactide and 25% 0056. For adequate distribution and absorption in the glycolide. As indicated, bioerodible copolymers are available patient, controlled release of the drug may occur at a desired in a wide range of molecular weights and ratios of lactic to site over a desired period of time. Advantageously, when the glycolic acid. biodegradable drug depot is implanted, controlled release of 0062) If not purchased from a supplier, then the biodegrad the drug is capable of being directed to sites which are deep, able polymers may be prepared by the procedure set forth in complicated, painful or dangerous to reach by conventional U.S. Pat. No. 4,293.539 (Ludwig, et al.), the disclosure of means and/or otherwise inaccessible. which is hereby incorporated by reference in its entirety. 0057 Polymer Depot for Control Release of Corticoster Ludwig prepares Such copolymers by condensation of lactic oids acid and glycolic acid in the presence of a readily removable 0058 Locally released low doses of corticosteroids can be polymerization catalyst (e.g., a strong acid ion-exchange delivered in a controlled and Sustained manner by dispersing resin such as Dowex HCR-W2-H). the steroid within a biocompatible biodegradable polymer 0063 Micro-Particles that breaks down over time within body tissues. Further, the 0064. In lieu of incorporating locally released low doses of implant or corticosteroid may be incorporated within a pro a corticosteroid in a homogenous biodegradable drug depot, tective coating that delays the release of the corticosteroid the drug depot can take the shape of Small biodegradable from the polymer matrix. The biocompatible biodegradable micro-particles, that is, formulating biodegradable micro polymer should preferably degrade by hydrolysis, by either particle that release a corticosteroidata rate not to exceed 100 surface erosion or by bulk erosion. However, surface erosion g/kg/day, 90 Lig/kg/day, 80 g/kg/day, 70 g/kg/day, 60 of the polymer depot may be preferred for some applications ug/kg/day, 50 lug/kg/day, 40 g/kg/day, 30 g/kg/day, 20 because it ensures that release of the locally delivered low ug/kg/day, and 10 g/kg/day (and every integer between 100 dose of the corticosteroid is not only sustained but has desir and 10). The release rate can also range from about 100 able release rates. ug/kg/day to about 1 pg/kg/day depending upon the specific 0059. Many biodegradable polymers may be used to activity of the compound at or near a site of a patient's pain. release corticosteroids to an inflammatory site. When the More specifically the corticosteroid being administered at a polymer and a corticosteroid are mixed together, the biode rate of about 50 lug/kg/day to about 100 pg/kg/day. Most gradable polymer incorporates the steroid into a polymer specifically the corticosteroid being administered at a rate of matrix for possible Sustained release of the drug at a target about 30 ug/kg/day to about 500 pg/kg/day. The manufacture area within the body. The biodegradable drug depot may of micro-particles or methods of making biodegradable degrade in vivo over a period of less than about two years, micro-particles are known in the art. Micro-particles from where at least 50% of the drug depot dissolves anywhere from any of the biodegradable polymers listed above can be made about 3 months to within about a year. by spray drying, solvent evaporation, phase separation, flu 0060. In one embodiment of the invention, the biodegrad idized bed coating or combinations thereof. able polymer may include, without limitation, natural or Syn 0065. With solvent evaporation, a corticosteroid, if thetic biocompatible biodegradable material. Natural poly soluble in organic solvents, may be entrapped in the biode mers include, but are not limited to, proteins such as albumin, gradable polymer by dissolving the polymer in a volatile collagen, gelatin synthetic poly(aminoacids), and prola organic solvent, adding a locally released low dose of a cor mines; glycosaminoglycans, such as hyaluronic acid and hep ticosteroid to the organic phase, emulsifying the organic arin; polysaccharides, such as alginates, chitosan, starch, and phase in water which contains a surfactant or polymer Such as dextans; and other naturally occurring or chemically modi polyvinyl alcohol, and finally removing the solvent under fied biodegradable polymers. Synthetic biocompatible biode vacuum to form discrete, hardened monolithic micro-par gradable materials include, but are not limited to the group ticles. comprising of poly(lactide-co-glycolide) (PLGA), polylac 0.066 Phase separation procedures entrap water-soluble tide (PLA), polyglycolide (PG), polyhydroxybutyric acid, agents in the polymer to prepare micro-particles. Phase sepa poly(trimethylene carbonate), polycaprolactone (PCL), poly ration involves coacervation of a biodegradable polymer. By Valerolactone, poly(alpha-hydroxy acids), poly(lactones), addition of a nonsolvent, such as silicone oil, the polymer is poly(amino-acids), poly(anhydrides), polyketals poly(ary then extracted from an organic solvent. lates), poly(orthoesters), poly(orthocarbonates), poly(phos 0067. Alternatively, the micro-particles may be prepared phoesters), poly(ester-co-amide), poly(lactide-co-urethane, by the process of Ramstack et al., 1995, described in pub polyethylene glycol (PEG), polyvinyl alcohol (PVA). PVA lished international patent application WO95/13799, the dis g-PLGA, PEGT-PBT copolymer(polyactive), methacrylates, closure of which is incorporated herein in its entirety. The poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), Ramstacket al. process essentially provides for a first phase, PEO-PPO-PAA copolymers, and PLGA-PEO-PLGA blends including an active agent and a polymer, and a second phase, and copolymers thereof and any combinations thereof. These that are pumped through a static mixer into a quench liquid to US 2008/031 7805 A1 Dec. 25, 2008 form micro-particles containing the active agent. The first and 0.000.1% and 99.9% or more, by weight, preferably between second phases can optionally be substantially immiscible and 0.5% and 60%, or more, by weight and more preferably the second phase is preferably free from solvents for the between 1% and 40%, or more, by weight. polymer and the active agent and includes an aqueous solu 0077. It is possible to tailor the drug depot to deliver a tion of an emulsifier. specified loading of a locally released low dose of corticos 0068. In a fluidized bedcoating, the drug is dissolved in an teroids by manipulating the percent drug incorporated in the organic solvent along with the polymer. The Solution is then polymer and the shape of the matrix or formulation, in addi processed, e.g., through a Wurster air Suspension coating tion to the form of the corticosteroid and the method of apparatus to form the final microcapsule product. production. The amount of drug released per day increases 0069. The biodegradable drug depot, can be prepared as proportionately with the percentage of drug incorporated into micro-particles in a size distribution range Suitable for local the formulation, e.g., matrix (for example, from about 1 to infiltration or injection. The diameter and shape of the micro about 50 to 90%). In the preferred embodiment, polymer particles can be manipulated to modify the release character matrices or other formulations with about 5-30% drug incor istics. For example, Smaller diameter micro-particles will porated are utilized, although it is possible to incorporate have faster release rates and increased tissue penetration for Substantially more drug, depending on the particular drug, the locally released low dose corticosteroids. However, larger method used for making and loading the device, and the diameter micro-particles will have the opposite effect. polymer. 0070. In addition, other particle shapes, such as, for 0078. As the biodegradable polymers undergo gradual example, cylindrical shapes, can also modify release rates of bio-erosion within bodily tissues or fluids, the corticosteroid a locally released low dose corticosteroid by virtue of the is released to the inflammatory site. The pharmacokinetic increased ratio of Surface area to mass inherent to such alter release profile of the corticosteroid by the biodegradable native geometrical shapes, relative to a spherical shape. The polymer depot may be first order, Zero order, bi- or multi diameter of injectable micro-particles are in a size range phasic, to provide desired treatment of inflammatory related from, for example, from about 1 microns to about 200 pain. In any pharmacokinetic event, the bio-erosion of the microns in diameter. In a more preferred embodiment, the polymer and Subsequent release of the corticosteroid may micro-particles range in diameter from about 5 to about 120 result in a controlled release of a corticosteroid from the microns. polymer matrix. The rate of release can range from about 100 0071 Biodegradable micro-particles that release a locally ug/kg/day to about 1 pg/kg/day depending upon the specific delivered low dose of corticosteroids may be emulsified in activity of the compound at or near a site of a patient's pain. Suitable aqueous or non-aqueous carriers which may include, Additional rates of release of the corticosteroid can include but is not limited to water, Saline, pharmaceutically accept from approximately 95ug/kg/day to approximately 10 pg/kg/ able oils, low melting waxes, fats, lipids, liposomes and any day; approximately 90 ug/kg/day to approximately 25 pg/kg/ other pharmaceutically acceptable Substance that is lipo day; approximately 85ug/kg/day to approximately 50 pg/kg/ philic, substantially insoluble in water, and is biodegradable day; approximately 80 ug/kg/day to approximately 75 pg/kg/ and/or eliminatable by natural processes of a patient's body. day; approximately 75 g/kg/day to approximately 100 Oils of plants such as Vegetables and seeds are included. pg/kg/day; approximately 70 ug/kg/day to approximately Examples include oils made from corn, sesame, cannoli, Soy 250 pg/kg/day; approximately 65 g/kg/day to approxi bean, castor, peanut, olive, arachis, maize, almond, flax, saf mately 500 pg/kg/day; approximately 60 g/kg/day to flower, Sunflower, rape, coconut, palm, babassu, and cotton approximately 750 pg/kg/day; approximately 55 ug/kg/day seed oil; waxes such as carnoba wax, beeswax, and tallow: to approximately 1 ng/kg/day; approximately 50 ug/kg/day to fats Such as triglycerides, lipids such as fatty acids and esters, approximately 10 ng/kg/day; approximately 45 g/kg/day to and liposomes such as red cell ghosts and phospholipid lay approximately 25 ng/kg/day; approximately 40 g/kg/day to CS. approximately 50 ng/kg/day; approximately 35 g/kg/day to 0072 Corticosteroid Loading of Biodegradable Polymer approximately 75 ng/kg/day; approximately 30 g/kg/day to 0073. When a locally delivered low dose of a corticoster approximately 100 ng/kg/day; approximately 25 ug/kg/day oid is admixed with a biodegradable polymer for a controlled to approximately 250 ng/kg/day; approximately 20 g/kg/ release into or near the site of a patient's pain, useful loadings day to approximately 500 ng/kg/day; and approximately 15 of said corticosteroid are from about 0.1% to about 99% ug/kg/day to approximately 750 ng/kg/day. In another (w/w) of the polymer, more preferably about 1% to about embodiment, the dosage of the corticosteroid is from approxi 80%, more preferably about 1% to about 50%, most prefer mately 15 lug/kg/day to approximately 50 pg/kg/day. In ably about 1% to about 30% of the polymer. another embodiment, the dosage is from approximately 10 0.074. When the corticosteroid is included with a suitable ug/kg/day to approximately 75 pg/kg/day. In another embodi vehicle in which microparticles comprising a locally deliv ment, the dosage is from approximately 5 ug/kg/day to ered low dose of a corticosteroid are Suspended, said corti approximately 100 pg/kg/day. In another embodiment, the costeroid is present, for example, in a weight percent relative dosage is from approximately 201g/kg/day to approximately to said corticosteroid from about 0.1% to about 99% (w/w) of 500 pg/kg/day. Alternatively, the rate of release can range the polymer, more preferably about 1% to about 80%, more from a rate of about 50 g/kg/day to about 100 pg/kg/day, and preferably about 1% to about 50%, most preferably about 1% even from about 30 lug/kg/day to about 500 pg/kg/day. to about 30% of the polymer. (0079 Excipients 0075 Release of the Locally Delivered Low Dosage Cor 0080. The release rate of the corticosteroid from a biode ticosteriod gradable polymer matrix can be modulated or stabilized by 0076 Locally delivered low doses of corticosteroids may adding a pharmaceutically acceptable excipient to the formu be incorporated into a biodegradable polymer or other con lation. An excipient may include any useful ingredient added trolled release formulations in a percent loading between to the biodegradable polymer depot that is not a corticosteroid US 2008/031 7805 A1 Dec. 25, 2008 or a biodegradable polymer. Pharmaceutically acceptable approximately 25 pg/kg/day; approximately 85 g/kg/day to excipients may include without limitation lactose, dextrose, approximately 50 pg/kg/day; approximately 80 g/kg/day to Sucrose, Sorbitol, mannitol, starches, gum acacia, calcium approximately 75 pg/kg/day; approximately 75 g/kg/day to phosphate, alginates, tragacanth, gelatin, calcium silicate, approximately 100 pg/kg/day; approximately 70 ug/kg/day microcrystalline cellulose, PEG, polyvinylpyrrolidone, cel to approximately 250 pg/kg/day; approximately 65 g/kg/ lulose, water, Sterile Saline, syrup, and methyl cellulose. An day to approximately 500 pg/kg/day; approximately 60 excipient for modulating the release rate of a corticosteroid ug/kg/day to approximately 750 pg/kg/day; approximately from the biodegradable drug depot may also include without 55 ug/kg/day to approximately 1 ng/kg/day; approximately limitation pore formers, pH modifiers, reducing agents, anti 50 ug/kg/day to approximately 10 ng/kg/day; approximately oxidants, and free radical scavengers. 45ug/kg/day to approximately 25 ng/kg/day; approximately I0081. Delivery of Corticosteroid by Polymer Depot 40 ug/kg/day to approximately 50 ng/kg/day; approximately 0082 Parenteral administration of a biodegradable com 35ug/kg/day to approximately 75 ng/kg/day; approximately position of the invention can be mainly effected by intramus cular injection. For most body spaces, the use of a needle may 30 ug/kg/day to approximately 100 ng/kg/day; approxi be acceptable. To inject the biodegradable drug depot into an mately 25 ug/kg/day to approximately 250 ng/kg/day; foramenal space, needles having a gauge of about 18-23 approximately 20 ug/kg/day to approximately 500 ng/kg/ gauge are suitable. However, if a needle/catheter combination day; and approximately 15 ug/kg/day to approximately 750 is chosen to deliver the biodegradable drug depot, then the ng/kg/day. In another embodiment, the dosage of the corti needles through which a catheter is introduced having gauge costeroid is from approximately 15 ug/kg/day to approxi sizes of about 16-18 gauge may be Suitable. mately 50 pg/kg/day. In another embodiment, the dosage is 0083. In another embodiment, the distalend of the catheter from approximately 10ug/kg/day to approximately 75 pg/kg/ may terminate just inside the foramenal space, for example day. In another embodiment, the dosage is from approxi within 3 cm of the nerve root. This embodiment may include mately 5 ug/kg/day to approximately 100 pg/kg/day. In the drug being released near the inflammatory pain site another embodiment, the dosage is from approximately 20 related to Sciatica. ug/kg/day to approximately 500 pg/kg/day. Alternatively, the 0084. For the polymer depot of the present invention, a rate of release can range from a rate of about 50 ug/kg/day to range of bore sizes is required for the application to various about 100 pg/kg/day, and even from about 30 ug/kg/day to body sites (e.g., 28 to 14 gauge). This flexibility also allows about 500 pg/kg/day. for the puncturing needle encased in a plastic infusion cath I0089. One example of a suitable pump is the Syn eter to be removable. For certain procedures that treat pain chroMed R (Medtronic, Minneapolis, Minn.) pump. This due to inflammation, thinner needles are used. Thinner pump has three sealed chambers. The first chamber contains needles have the same bores but are longer, and hence look an electronic module and battery. The second chamber con thinner. tains a peristaltic pump and drug reservoir. The third chamber 0085 Administration of a corticosteroid via a polymer contains an inert gas, which provides the pressure needed to depot delivers the drug precisely to a specific area of the body. force the drug into the peristaltic pump. To fill the pump, the As such, one may avoid or minimize adverse events to the drug is injected through the reservoir fill port to the expand patient. able reservoir. I0086) Delivery of Corticosteroid by a Drug Pump 0090 The inert gas creates pressure on the reservoir, and 0087. A locally released low dose of corticosteroid may be the pressure forces the drug through a filter and into the pump delivered locally to the target area by a drug pump. The pump chamber. The drug is then pumped out of the device from the delivers the drug continuously and precisely to a specific area pump chamber and into the catheter, which will direct the of the body. This assembly may avoid or minimizes adverse drug to the target site, i.e., a location at or near the site of a events to the patient, Such as nausea or addiction to oral patient's pain. medications. (0091. Therate of delivery of the drug may be controlled by 0088. The controlled administration of a locally delivered a microprocessor. This allows the pump to be used to deliver low dose of corticosteroid may include, for example, an infu similar or different amounts of the drug, at specific times, or sion pump or an implantable mini-pump inserted at the target at set intervals between deliveries, thereby controlling the site, or an implantable controlled release device (such as, for release rates to correspond with the desired targeted release example, the device described in U.S. Pat. No. 6,001,386), or rates. a Sustained release delivery system (such as the system 0092 Alternatively, other devices suited for drug delivery described in U.S. Pat. No. 6,007,843). The administration can also be used to deliver a locally released low dose of a system may provide targeted release rates of the drug at or corticosteroid at or near the site of a patient's pain. Delivery near the site of a patient's pain, where the pump locally devices that may be suitable for adaptation for the method of releases a low dose of a corticosteroid at a rate that Substan the invention includebutare not limited to, for example, those tially matches a pre-selected targeted release rate. This devices found in U.S. Pat. No. 6,551,290 (Elsberry, et al.), release rate is not to exceed 100 g/kg/day, 90 ug/kg/day, 80 which describes a medical catheter for targeted, specific drug ug/kg/day, 70 ug/kg/day, 60 ug/kg/day, 50 g/kg/day, 40 delivery; U.S. Pat. No. 6,571,125 (Thompson), which g/kg/day, 30 g/kg/day, 201g/kg/day, and 10 g/kg/day (and describes an implantable medical device for controllably every integer between 100 and 10). The rate of release can releasing a biologically-active agent; U.S. Pat. No. 6,594,880 range from about 100 g/kg/day to about 1 pg/kg/day depend (Elsberry), which describes an intraparenchymal infusion ing upon the specific activity of the compoundator near a site catheter system for delivering therapeutic agents to selected of a patient's pain. Additional rates of release of the corticos sites in an organism; and U.S. Pat. No. 5,752.930 (Rise, et al.), teroid can include from approximately 95 ug/kg/day to which describes an implantable catheter for infusing equal approximately 10 pg/kg/day; approximately 90 g/kg/day to Volumes of agents to spaced sites. US 2008/031 7805 A1 Dec. 25, 2008

0093. Additional designs which may be adaptable to be until the polymer and drug appear uniformly mixed. Next, employed in the method of the present invention are provided, 0.46 grams of polyethylene glycol methyl ether (MW 550, for example, in U.S. Pat. No. 6,913,763 to Lerner, involving Sigma-Aldrich, St. Louis, Mo.) are added to the drug and a pre-programmable implantable apparatus with a feedback polymer mixture. The components are mixed using a spatula, regulated delivery method. US patent application 2004/ until the mixture appears homogeneous. 0106914 involving a micro-reservoir osmotic release system 0100. The mixture is then loaded into a HAAKE MiniDab for controlled release of chemicals, U.S. Pat. No. 7,144,384 to Rheomex extruder (Model CTW5, Thermo Electron Corp, Gorman et al., involving a small, light-weight device for Waltham, Mass.), and is extruded through a die of 0.75 mm delivering liquid medication, US 2004/0082908 involving an diameter (temperature 120°C., 25 rpm). The resulting poly implantable micro-miniature infusion device, U.S. Pat. No. meric strand is then cut into cylindrical pellets approximately 6,979,351 to Forsell, involving an implantable ceramic valve 0.75 mm in length (aspect ratio=1). The cut pellets are stored pump assembly, and US 2004/0065615 involving an implant in a sealed glass vial, which had been purged with dry nitro able infusion pump with a collapsible fluid chamber. Alzet(R) gen, until needed. osmotic pumps (Durect Corporation, Cupertino, Calif.) are 0101. Approximately 25 mg of the pellets are weighed also available in a variety of sizes, pumping rates and dura into each of 3 vials containing 10 mL of phosphate buffered tions suitable for use in the method of the present invention. saline, 0.5% SDS (pH 7.4). The vials are sealed and are placed 0094 Based upon the condition, such as severity and dura in a Model C24 incubator/shaker (New Brunswick Scientific tion of pain, a physician, Veterinarian, or an appropriate Co., Edison, N.J.) set at 37° C. and are agitated at approxi health care professional, or the patient, based upon the con mately 70 RPMs. At specific time points, the elution buffer is dition, for example, the severity and duration of pain, may removed and is analyzed for drug using a UV/Vis spectro determine the local administration rate of the low dose corti photometer at 240 nm (Model: Lambda 850, Perkin Elmer, costeroid at or near the site of a patient's pain. The duration of Waltham, Mass.). The sample vials are replenished with fresh administration of the steroid, interval between locally buffer and are returned to the incubator/shaker until the next released doses, the size of the low dose, continuity or spon time point. The cumulative drug released is plotted as a per taneity of dosage administration, are all appropriately deter centage of the initial drug payload. mined by the physician, Veterinarian, or other health care 0102 Before 20 days, less than 10% (cumulative) of the professional. fluocinolone elutes from the depot. On day 20, slightly more 0095. The health care professional has options in admin than 10% (cumulative) of the fluocinolone elutes. By day 40, istering the drug at or near the site of a patient's pain. An approximately 15% (cumulative) of the fluocinolone elutes effective amount of a locally released low dose of a corticos from the depot. By day 60, approximately 20% (cumulative) teroid and one or more additional therapeutic agents, wherein of the fluocinolone elutes from the depot. the locally administered low dose of corticosteroids and or 0103 Preparation and Release Rates of 15% Dexametha one more additional therapeutic agents, maybe administered Sone in PLGA Pellets by a drug pump. 0104. To prepare biodegradable drug depot of PLGA con 0096. The drug pump's release of the locally administered taining 15% dexamethasone, approximately 50 grams of low dose of a corticosteroid can (1) be localized and Sus 85/15 poly(D.L-lactide-co-glycolide) (PLGA) (Lakeshore tained, (2) occur over a period of at least one day to about 12 Biomaterials, Birmingham, Ala.) with IV of 0.75 dL/g and months, or (3) be continuous or periodic. Further, the health molecular weight of 117 kDa, are placed in a polypropylene care provider has the choice of selecting a pharmaceutical beaker and cooled with liquid nitrogen (approximately 200 composition having a targeted release rate. For example, a mL) for 10 minutes. The polymer is then ground into fine targeted release rate may be from about 2 weeks to about 12 particles of approximately 80 microns average diameter months. The health care provider may vary the combinations using an Ultra Centrifugal Mill ZM 200 (Retsch GmbH & as the patient provides feedback over the treatment course. Co., Haan, Germany). The ground polymer particles are col Accordingly, the health care provider has numerous options lected and are placed in 10 cm aluminum weigh pans. The not previously available, especially for the treatment of pain, pans are placed in a vacuum oven at 35°C. under vacuum for particularly chronic pain. 24 hours to remove any condensation resulting from the grinding process. EXAMPLES 0105 Next, 3.0 grams of polymer are weighed into an 0097. Preparation and Release Rates of 15% Fluocinolone aluminum weigh pan using an analytical balance. Then 0.6 Acetonide in PLGA Pellets grams of dexamethasone (Spectrum Chemical, Gardena, 0098. To prepare biodegradable drug depot of PLGA con Calif.) are added. The components are stirred using a spatula taining 15% fluocinolone, approximately 50 grams of 85/15 until the polymer and drug appear uniformly mixed. 0.41 poly(D.L-lactide-co-glycolide) (PLGA) (Lakeshore Bioma grams of polyethylene glycol methyl ether (MW 550, Sigma terials, Birmingham, Ala.) with IV of 0.75 dL/g and molecu Aldrich, St. Louis, Mo.) are then added to the drug and poly lar weight of 117 kDa, are placed in a polypropylene beaker mer mixture. The components are mixed using a spatula, until and cooled with liquid nitrogen (approximately 200 mL) for the mixture appeared homogeneous. 10 minutes. The polymer is then ground into fine particles of 01.06 The mixture is then loaded into a HAAKE MiniDab approximately 80 microns average diameter using an Ultra Rheomex extruder (Model CTW5, Thermo Electron Corp., Centrifugal Mill ZM 200 (Retsch GmbH & Co., Haan, Ger Waltham, Mass.), and is extruded through a die of 0.75 mm many). The ground polymer particles are collected and are diameter (temperature 120°C., 25 rpm). The resulting poly placed in 10 cm aluminumweigh pans. The pans are placed in meric strand is then cut into cylindrical pellets approximately a vacuum oven at 35°C. under vacuum for 24 hours to remove 0.75 mm in length (aspect ratio=1). The cut pellets are stored any condensation resulting from the grinding process. in a sealed glass vial, which had been purged with dry nitro 0099 Next, 3.5 grams of polymer are weighed into an gen, until needed. aluminum weigh pan using an analytical balance. 0.7 grams 0107. Approximately 25 mg of the pellets are weighed of fluocinolone acetonide (Spectrum Chemical, Gardena, into each of 3 vials containing 10 mL of phosphate buffered Calif.) are added. The components are stirred using a spatula saline, (pH 7.4). The vials are sealed and placed in a Model US 2008/031 7805 A1 Dec. 25, 2008

C24 incubator/shaker (New Brunswick Scientific Co., Edi indicates a positive response. The testing continues for four son, N.J.) set at 37° C. and are agitated at approximately 70 additional measurements and is used to calculate the response RPMs. At specific time points, the elution buffer is removed threshold. Four consecutive positive responses receive a score and is analyzed for drug using a UV/Vis spectrophotometer at of 0.25 g, and five consecutive negative responses (i.e., no 242 nm (Model: Lambda 850, Perkin Elmer, Waltham, paw withdrawal) receives a score of 15 g. The mechanical Mass.). The sample vials are replenished with fresh buffer paw withdrawal threshold of each animal is measured one day and are returned to the incubator? shaker until the next time prior to Surgery (per-Surgical baseline) and on Days 8, 15, and point. The cumulative drug released is plotted as a percentage 22. of the initial drug payload. 0115 The 50% paw withdrawal threshold is calculated 0108. At 2 days, about 10% (cumulative) of the drug was (PWT Luo and Calcutt, 2002, Chaplanet al. 1994) using the eluted. By 10 days, slightly less than 20% (cumulative) of the formula 10 (Xf-?d)/10,000, where Xf is the final von Frey drug was eluted. By 20 days, only slightly more than 20% filament used (log units), ? is a value that analyzes the (cumulative) of the drug was eluted. The amount of drug response pattern (taken from the table published by Chaplan eluted increased gradually to approximately 27% (cumula at al., 1994), and dis the mean difference between stimuli (log tive) by date 60. units). Data is analyzed using one-way ANOVA on each test. 0109 Dose Reduction Study of Systemically Adminis 0116. All animals, regardless of the treatment group, tered Fluocinolone in the Rat Chronic Constriction Injury develop posture abnormalities (i.e., in walking and paw pos Model ture), following CCI of the sciatic nerve. All animals display 0110. The purpose of this study is to evaluate the efficacy guarding behavior (i.e., protecting the injured paw), and they of fluocinolone acetonide (Sigma Catil F8880-25MG; Sigma place their toes together instead of spreading them apart, as Aldrich, St. Louis, Mo.), a potent corticosteroid, to reduce normally seen in naive animals. A pronounced limp is often neuropathic pain in an animal model. This animal model evident, and some animals elevated the CCI-affected paw for involves pain-associated behaviors in male Wistar rats (300 prolonged periods during the first few days (1-6) after Sur 326 g) following chronic constriction injury (CCI) induced by gery. The posture abnormalities are used to minimize or avoid a procedure similar to that described by Bennett and Xie sensory stimulation. (1988). Under 2% isoflurane anesthesia, the rat’s common 0117 Tables 1A and 1B summarize the thermal paw with sciatic nerve is exposed and freed from adherent tissue at drawal latencies and Von Frey threshold responses, respec mid-thigh by separating the muscle (biceps femoris) by blunt tively, as a percentage of the pre-CCI baseline value for each dissection. Four loose ligatures are placed 1 mm apart, using behavioral test for animals treated with fluocinolone at doses chromic gut (4-0 absorbable Suture, Jorgensen Laboratories, of 0.5, 5, or 25 g/kg. Inc. Loveland, Colo.). 0111. After CCI induction, each group (n=7) receive treat TABLE 1A ment via systemic injection. Vehicle control animals (Group 1) receive 1x phosphate buffered solution (PBS) intraperito Thermal Paw Withdrawal neally (IP) every three days, beginning the day of Surgery Fluocinolone Latencies as Percent Baseline (Day 0), etanercept (Group 2: 3 mg/kg) is administered IP Treatment Dose Level every 3 days beginning Day 0. Animals intreatment Groups3. 4 and 5 receive fluocinolone (0.5, 5, or 25 g/kg) subcutane IP Every DAY 0.5 g/kg 5 g/kg 25 Lig/kg ously (SC) every day beginning Day 0. Day 7 Mean 71.6 79.7 674 0112 Thermal hyperalgesia is measured using a plantar SE 4.6 4.8 3.9 N 7 7 7 analgesia instrument (Stoelting, Wood Dale, Ill.). Prior to Day 14 Mean 70.8 83.8 80.9 testing, each animal is placed on the plantar test apparatus, a SE 2.4 3.7 4.1 clear plastic chamber, and is allowed to rest/acclimate for 15 N 5 7 7 minutes. A radiant (heat) beam stimulus is applied to the CCI Day 21 Mean 63.1 80.2 8O.O paw of each animal. After paw withdrawal, an automated SE 4.1 3.0 S.O control interrupts both the stimulus and the timer. The heat N 5 7 7 source device is set at intensity 50, and a maximal cut-offat 15 seconds is set to prevent tissue damage. Thermal hyperalgesia paw withdrawal latency response of the injured site (right hind paw) of each animal is measured 2 days prior to CCI TABLE 1B Surgery (pre-injury baseline) on Days 7, 14, and 21 after Von Frey Filament Allodynia surgery. Data from each test is analyzed by one-way ANOVA. Fluocinolone Latencies as Percent of Baseline 0113 Mechanical allodynia is measured using von Frey monofilament test (Stoelting, Wood Dale, Ill.). The plantar Treatment Dose Level surface of the CCI paw of each animal is tested as described IP Every DAY 0.5 g/kg 5 g/kg 25 Lig/kg by Chaplanetal. (1994). Each animal is placed in a suspended Day 8 Mean 45.2 54.8 76.3 clear plastic chamber with a wire mesh bottom. Prior to SE 9.5 6.8 20.6 testing, each animal is acclimated for 15 minutes. The 50% N 7 7 7 paw withdrawal threshold response is determined by sequen Day 15 Mean 47.1 57.5 68.9 tially increasing or decreasing the stimulus strength accord SE 8.1 6.7 11.7 ing to the “up-down method of Dixon (1980). N 5 7 7 0114 Testing begins with a filament with a buckling Day 22 Mean 66.2 55.2 70.3 weight of 2.0 g and continued through a series of filaments SE 32.8 11.7 13.2 applied in sequence, up to about 15 g. Each filament is applied N 5 7 7 with enough pressure to cause a buckle effect. The absence of apaw lifting/withdrawal response after 5 seconds prompts the 0118 Fisher LSD tests are performed to compare each use of the filament to the next higher weight. Paw withdrawal, group to vehicle controls and to one another for Days 7, 14. US 2008/031 7805 A1 Dec. 25, 2008

and 21. The results reveal that across all test days, the three Inc., Somerville, N.J.) within the muscle in the perineural doses of fluocinolone produce an increase in thermal latency space with the catheter tip as perpendicular as possible and relative to vehicle controls (Fisher LSD, p<0.05). On Day 7, proximate to the Sciatic nerve but without touching the nerve. the LSD results indicate that the 5ug/kg dose is significantly The proximal end of the catheter is attached to the loaded more effective than 25 ug/kg dose (Fisher LSD, p<0.05). On osmotic infusion pump. The pump and catheter are tunneled Days 14 and 21, both the 5 and 25 ug/kg doses are signifi up through the same incision under the skin and left in the SC cantly more effective than the 0.5 g/kg dose (Fisher LSD, space on the animal's back between the Scapulae. The inci p<0.05). Both the 5 and 25 ug/kg doses produce similar sion is then closed with Surgical clips. effects (Fisher LSD, ps-0.05, n.s.). 0.125 Under aseptic conditions and 2% isofluorane anes 0119 The data from this study indicate that fluocinolone thesia, a small incision is made between the Scapulae of the administered at doses of 0.5, 5, and 25 g/kg/day significantly animal's back (directly above the pump) to exchange the increases the paw withdrawal latency period following ather pump reservoir on Day 10. mal stimulus when compared to vehicle control group 0.126 Pump reservoirs are recovered on Days 10 and 22. (ANOVA: F(3,24)=37.21, p<0.05). In addition, fluocinolone Residual pump Volumes are collected, measured, stored at at 5 and 25ug/kg/day improves thermal hyperalgesia signifi -20°C., until analyzed. Serum samples are obtained on Days cantly greater than etanercept on all days tested (ANOVA: 0, 5, 12, 17, and 22. Under 2-5% anesthesia, blood is taken p<0.05). Fluocinolone at 0.5ug/kg/day also tends to improve from the retro-orbital plexus (0.5 ml of blood) from all ani thermal latencies over etanercept; however, these improve mals. Blood is collected, allowed to coagulate in serum sepa ments are only statistically significant on Day 7 (ANOVA: rator test tubes, and processed by centrifugation at 3000 rpm p<0.05). The data indicate that administration offluocinolone for 10 minutes. at doses of 0.5, 5, or 25 ug/kg/day SC significantly improves 0127. Fluocinolone is administered at doses of 0.0032 (overall ANOVA) mechanical allodynia when compared to ng/hour (0.02304 ng/kg/day), 0.016 ng/hour (0.1152 ng/kg/ vehicle controls. In addition, the results suggest that the three day), and 0.08 ng/hour (0.576 ng/kg/day). Dexamethasone is doses of fluocinolone tend to improve mechanical allodynia administered at 2.0 ng/hour (14.4 ng/kg/day), 10 ng/hour (72 overetanercept; however, these improvements are not statis ng/kg/day), and 50 ng/hour (360 ng/kg/day). 0.5ul/hour PBS tically significant. is administered as the negative control. Thermal hyperalge 0120 Daily SC administration of 25 ug/kg fluocinolone sia, induced and measured as described above, is measured on for 21 days results in a significant decrease in body weight Days -2, 7, 14, and 21. Mechanical allodynia, induced and gain (~50 g. body weight difference by Day 22) when com measured as described above, is measured on Days -1, 8, 15, pared to vehicle controls. The body weight gain in this group and 22. is consistently lower than vehicle controls starting on Day 5 I0128. All animals, regardless of the treatment group, (~10 g difference) and remains lower (-50g difference) until exhibit posture abnormalities, guarding behavior, and a pro the end of the study. Daily SC administration of 0.5 or 5ug/kg nounced limp as described above. Some animals elevate the fluocinolone for 21 days does not have any effect on body CCI-affected paw for prolonged periods during the first few Weight gain. days (1-6) after Surgery. These defensive posture abnormali 0121. In summary, the overall ANOVA indicates that fluo ties are seen in all groups. The observed “pain' features cinolone produces a significant increase in thermal latency Suggest that animals are sensitive to stimulations as a result of F(3,24)=8.40, p<0.05. The 0.5ug/kgt-test results compared the CCI, and that the posture abnormalities are used to mini to etanercept, show a significant increase in latency on Day 7 mize or avoid sensory stimulation. In addition, none of these (Day 7 (12)=-3.35, p<0.05); but not on Days 14 and 21 animals appear to have any posture abnormalities (i.e., in (Day 14 (12)=-1.54, n.s.); Day 21 (12)=0.0, n.s.). The 5 walking and paw posture) due to the catheter pump implant. ug/kg t-test results show a significant increase in latency on I0129. The results of the thermal paw withdrawal latency all testing days: Day 7(12)=-4.58, p<0.05: Day 14 (12)=- tests are disclosed in FIG. 1. As is evident from this figure, 3.82, p<0.05; and Day 21 (12)=-2.18, p<0.05). When com 2.0, 10, and 50 ng/hour of dexamethasone, for all three days paring the mechanical thresholds of fluocinolone to etaner tested, increases time until withdrawal compared to PBS. cept, the overall ANOVA does not reveal any significant Similarly, fluocinolone at dosages of 0.0032, 0.016, and 0.08 differences (F3, 24=+0.67, n.s.). ng/hour produce increases in the thermal paw withdrawal 0122) Pump Delivery of Fluocinolone and Dexametha latency tests compared to PBS. The results for both drugs are sone in the Rat Chronic Constriction Injury Model statistically significant (p<0.05). 0123. Following the above experiments, the efficacy of 0.130. The results of the von Frey threshold response tests locally administered, low dose of fluocinolone acetonide are disclosed in FIG. 2. For this test, all three dosages of (Sigma Cath F8880-25MG: Loti 043K1167, Sigma Aldrich) dexamethasone provide increases in the mechanical thresh and dexamethasone (Sigma Aldrich) is examined in the same old for the rats, except for 10 ng/hour at Day 15, 50 ng/hour at CCI rat model. CCI surgery is conduced as described above, Day 15, and 50 ng/hour at Day 22. In addition, all three and the rats are randomly assigned to 1 of 7 treatment groups dosages of fluocinolone provide increases in the mechanical (n=7). threshold for the rats for each day tested. However, the results 0.124. After each CCI surgery is completed, all animals, of these tests are not statistically significant. including controls, are implanted with an Alzet(R) osmotic I0131 Although the invention herein has been described mini-pump (volume rate 0.5 ul/h) (Model 2002-Lot No. with reference to particular embodiments, it is to be under 10125-05, Durect Corp., Cupertino, Calif.) connected to a stood that these embodiments are merely illustrative of the catheter (sterile catheters with suture loops) to allow for local principles and applications of the present invention. For administration of dexamethasone, fluocinolone, or PBS start example, a person of ordinary skill in the art will appreciate ing the day of injury (Day 0). The distal catheter tip is that the concepts of the DNA constructs according to any anchored with Prolene suture (4-0, non-absorbable, Ethicon, embodiment of the instant invention, as well as methods and US 2008/031 7805 A1 Dec. 25, 2008

systems for delivery of these DNA constructs can be applied ethasone, flumethasone, diflorasone, clobetasol, cortisone, to other diseases, including, without limitations, diseases of paramethasone, clocortolone, prednisolone 21-hemisucci the myocardium, peripheral nervous system, organs (diabe nate free acid, prednisolone metasulphobenzoate, predniso tes), diseases of the spine and joints, and complex diseases lone terbutate, and triamcinolone acetonide 21-palmitate. Such as obesity without excessive experimentation. It is there 4. The composition of claim 1 wherein said corticosteroid fore to be understood that numerous modifications may be is fluocinolone. made to the illustrative embodiments and that other arrange 5. The composition of claim 1 wherein said corticosteroid ments may be devised without departing from the spirit and is dexamethoSone. scope of the present invention as defined by the following 6. The composition of claim 1 wherein said pain is associ claims. ated with a condition selected from the group consisting of an 0132 All publications cited in the specification, both inflammatory disease, inflammation, Sciatica, herniated disc, patent publications and non-patent publications, are indica Stenosis, mylopathy, low back pain, facet pain, osteoarthritis, tive of the level of skill of those skilled in the art to which this rheumatoid arthritis, osteolysis, tendonitis, carpal tunnel Syn invention pertains. All these publications are herein fully drome, and tarsal tunnel syndrome. incorporated by reference to the same extent as if each indi 7. The composition of claim 1 wherein said site of pain vidual publication were specifically and individually indi includes a Surgical site, epidural spaces, perinureal spaces, cated as being incorporated by reference. foramenal spaces, or the dorsal root ganglia. What we claim is: 8. A composition for the reduction of pain in a mammal 1. A composition for the treatment of pain in a mammal comprising an biocompatible biodegradable polymer and a comprising an biocompatible biodegradable polymer and a corticosteroid wherein said biocompatible biodegradable corticosteroid wherein said biocompatible biodegradable polymer releases said corticosteroid at a rate not to exceed 50 polymer releases said corticosteroid at a rate not to exceed ug per kg of body weight of said mammal per day, wherein 100 ug per kg of body weight of said mammal per day, said corticosteroid is released at or near the site of pain in said wherein said corticosteroid is released at or near the site of mammal. pain in said mammal. 9. The composition of claim 8 wherein said biocompatible 2. The composition of claim 1 wherein said biocompatible biodegradable polymer is selected from the group consisting biodegradable polymer is selected from the group consisting of albumin, collagen, gelatin, synthetic poly(aminoacids), of albumin, collagen, gelatin, synthetic poly(aminoacids), prolamines, glycosaminoglycans, hyaluronic acid, heparin prolamines, glycosaminoglycans, hyaluronic acid, heparin polysaccharides, alginates, chitosan, Starch, dextans, poly polysaccharides, alginates, chitosan, starch, dextans, poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polygly (lactide-co-glycolide) (PLGA), polylactide (PLA), polygly collide (PG), polyhydroxybutyric acid, poly(trimethylene car collide (PG), polyhydroxybutyric acid, poly(trimethylene car bonate), polycaprolactone (PCL), polyvalerolactone, poly bonate), polycaprolactone (PCL), polyvalerolactone, poly (alpha-hydroxy acids), poly(lactones), poly(amino-acids), (alpha-hydroxy acids), poly(lactones), poly(amino-acids), poly(anhydrides), polyketals poly(arylates), poly(orthoe poly(anhydrides), polyketals poly(arylates), poly(orthoe sters), poly(orthocarbonates), poly(phosphoesters), poly(es sters), poly(orthocarbonates), poly(phosphoesters), poly(es ter-co-amide), poly(lactide-co-urethane, polyethylene glycol ter-co-amide), poly(lactide-co-urethane, polyethylene glycol (PEG), polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT (PEG), polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropy copolymer(polyactive), methacrylates, poly(N-isopropy lacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA lacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA blends, copolymers thereof, copolymers, PLGA-PEO-PLGAblends, copolymers thereof, and combinations thereof. and combinations thereof. 10. The composition of claim 8 wherein said corticosteroid 3. The composition of claim 1 wherein said corticosteroid is selected from the group consisting of dexamethasone, is selected from the group consisting of dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, tri betamethasone, triamcinolone, triamcinolone acetonide, tri amcinolone diacetate, triamcinolone hexacetonide, beclom amcinolone diacetate, triamcinolone hexacetonide, beclom ethasone, beclomethasone dipropionate, beclomethasone ethasone, beclomethasone dipropionate, beclomethasone dipropionate monohydrate, flumethasone pivalate, diflo dipropionate monohydrate, flumethasone pivalate, diflo rasone diacetate, fluocinolone acetonide, fluorometholone, rasone diacetate, fluocinolone acetonide, fluorometholone, fluorometholone acetate, clobetasol propionate, des fluorometholone acetate, clobetasol propionate, des Oximethasone, fluoxymesterone, fluprednisolone, hydrocor Oximethasone, fluoxymesterone, fluprednisolone, hydrocor tisone, hydrocortisone acetate, hydrocortisone butyrate, tisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone sodium phosphate, hydrocortisone sodium hydrocortisone sodium phosphate, hydrocortisone sodium Succinate, hydrocortisone cypionate, hydrocortisone probu Succinate, hydrocortisone cypionate, hydrocortisone probu tate, hydrocortisone Valerate, cortisone acetate, parametha tate, hydrocortisone Valerate, cortisone acetate, parametha Sone acetate, methylprednisolone, methylprednisolone Sone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium Succinate, prednisolone, acetate, methylprednisolone sodium Succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, pred prednisolone acetate, prednisolone sodium phosphate, pred nisolone tebutate, clocortolone pivalate, fluocinolone, dex nisolone tebutate, clocortolone pivalate, fluocinolone, dex amethasone 21-acetate, betamethasone 17-Valerate, isoflu amethasone 21-acetate, betamethasone 17-Valerate, isoflu predone, 9-fluorocortisone, 6-hydroxydexamethasone, predone, 9-fluorocortisone, 6-hydroxydexamethasone, dichlorisone, meclorisone, flupredidene, doxibetasol, halo dichlorisone, meclorisone, flupredidene, doxibetasol, halo predone, halometasone, clobetaSone, diflucortolone, isoflu predone, halometaSone, clobetaSone, diflucortolone, isoflu predone acetate, fluorohydroxyandrostenedione, beclom predone acetate, fluorohydroxyandrostenedione, beclom ethasone, flumethasone, diflorasone, clobetasol, cortisone, US 2008/031 7805 A1 Dec. 25, 2008

paramethasone, clocortolone, prednisolone 21-hemisucci 19. The method of claim 14 wherein the site includes a nate free acid, prednisolone metasulphobenzoate, predniso Surgical site, epidural spaces, perinureal spaces, foramenal lone terbutate, and triamcinolone acetonide 21-palmitate. spaces, or the dorsal root ganglia. 11. The composition of claim 8 wherein said corticosteroid 20. The method of claim 14 wherein the corticosteroid is is fluocinolone or dexamethosone. selected from the group consisting of dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, tri 12. The composition of claim 8 wherein said pain is asso amcinolone diacetate, triamcinolone hexacetonide, beclom ciated with a condition selected from the group consisting of ethasone, beclomethasone dipropionate, beclomethasone an inflammatory disease, inflammation, Sciatica, herniated dipropionate monohydrate, flumethasone pivalate, diflo disc, Stenosis, mylopathy, low back pain, facet pain, osteoar rasone diacetate, fluocinolone acetonide, fluorometholone, thritis, rheumatoid arthritis, osteolysis, tendonitis, carpaltun fluorometholone acetate, clobetasol propionate, des nel syndrome, and tarsal tunnel syndrome. Oximethasone, fluoxymesterone, fluprednisolone, hydrocor 13. The composition of claim 8 wherein said site of pain tisone, hydrocortisone acetate, hydrocortisone butyrate, includes a Surgical site, epidural spaces, perinureal spaces, hydrocortisone sodium phosphate, hydrocortisone sodium foramenal spaces, or the dorsal root ganglia. Succinate, hydrocortisone cypionate, hydrocortisone probu tate, hydrocortisone Valerate, cortisone acetate, parametha 14. A method for treating pain in a mammal comprising Sone acetate, methylprednisolone, methylprednisolone selecting a site for the local delivery of a corticosteroid plac acetate, methylprednisolone sodium Succinate, prednisolone, ing in or on the mammal an implant for delivering the corti prednisolone acetate, prednisolone sodium phosphate, pred costeriod at the site; wherein said implant releases said cor nisolone tebutate, clocortolone pivalate, fluocinolone, dex ticosteriod at a rate not to exceed about 100 ug per kg of body amethasone 21-acetate, betamethasone 17-Valerate, isoflu weight of said mammal per day. predone, 9-fluorocortisone, 6-hydroxydexamethasone, 15. The method of claim 14 wherein said implant is a dichlorisone, meclorisone, flupredidene, doxibetasol, halo biodegradable drug depot comprising the corticosteroid and a predone, halometasone, clobetaSone, diflucortolone, isoflu biodegradable polymer. predone acetate, fluorohydroxyandrostenedione, beclom ethasone, flumethasone, diflorasone, clobetasol, cortisone, 16. The method of claim 15, wherein placing the biode paramethasone, clocortolone, prednisolone 21-hemisucci gradable drug depot at the site includes using a Syringe and nate free acid, prednisolone metasulphobenzoate, predniso needle, a catheter, or a canula. lone terbutate, and triamcinolone acetonide 21-palmitate. 17. The method of claim 14 wherein the implant comprises 21. The method of claim 14 wherein the corticosteroid is a drug pump, the corticosteroid, and a catheter wherein said fluocinolone or dexamethasone. catheter delivers said corticosteroid from said pump to said 22. A method for reducing pain in a mammal comprising site of pain. selecting a site for the local delivery of a corticosteroid plac 18. The method of claim 14, wherein the pain is associated ing in or on the mammal an implant for delivering the corti with a condition selected from the group consisting of an costeriod at the site; wherein said implant releases said cor inflammatory disease, inflammation, Sciatica, herniated disc, ticosteriod at a rate not to exceed about 50 ug per kg of body Stenosis, mylopathy, low back pain, facet pain, osteoarthritis, weight of said mammal per day. rheumatoid arthritis, osteolysis, tendonitis, carpal tunnel Syn drome, and tarsal tunnel syndrome. c c c c c