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. E Day 7 8 Day 14 El Day 21 3OO 2OO OO OO Control Dexamethasone DexamethasOne Dexamethasone Fuocinolone Fluocinolone Fuocinolone 2.0 ng/hr 1Ong/hr 50 ng/hr 0.0032ng/hr 0.016 ng/hr 0.08 ng/hr Patent Application Publication Dec. 25, 2008 Sheet 1 of 2 US 2008/0317805 A1 900 ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 80.0 - 7OO – 6OO - 5OO - E Day 7 EDay 14 40.0 - : El Day 21 2OO - OO = OO – Dexamethasone Dexamethasone Dexamethasone Fuocinolone Fluocinolone Fuocinolone 2.0 ng/hr 1Ong/hr 50 ng/hr O.OO32ng/hr O.016 ng/hr 0.08 nghr Patent Application Publication Dec. 25, 2008 Sheet 2 of 2 US 2008/0317805 A1 Figure 2 14OO - 2OO - 1OOO - 8OO - E Day 8 8 Day 15 E Day 22 6OO - 4OO - 2OO - OO Control Dexamethasone Dexamethasone Dexamethasone Fuocinolone Fluocinolone Fluocinolone 2.0 ng/hr 10 ng/hr 50 ng/hr 0.0032ng/hr 0.016 ng/hr 0.08 ng/hr US 2008/031 7805 A1 Dec. 25, 2008 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