Transdiscal administration of inhibitors of p38 MAP kinase

1 . A method of treating degenerative disc disease in an intervertebral disc having a nucleus pulposus and an annulus fibrosus, comprising transdiscally administering an effective amount of a formulation comprising a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is selected from the group consisting of:

i) an aryl-pyridinyl heterocycle and

ii) an indol-5-carboxamide.

2 . The method of claim 1 wherein the p38 MAP kinase inhibitor is selected from the group consisting of:

i) diaryl imadazole;

ii) N,N′-diaryl urea;

iii) N,N-diaryl urea;

iv) benzophenone;

v) pyrazole ketone;

vi) indole amide;

vii) diamides;

viii) quinazoline;

ix) pyrimido [4,5-d]pyrimidinone;

x) pyridylamino-quinazolines;

xi) JNJ 3026582 (RWJ 67657);

xii) JNJ 17089540 (RWJ 669307);

xiii) JNJ 7583979 (RWJ 351958);

xiv) SCIO-282 (SD 282); and

xv) SCIO-469 (SD 469).

3 . A method of inhibiting TNFα-induced glycosaminoglycan release in an intervertebral disc having a nucleus pulposus and an annulus fibrosus, comprising transdiscally administering an effective amount of a formulation comprising a p38 MAP kinase inhibitor and a TNFα antagonist into an intervertebral disc, wherein the p38 MAP kinase inhibitor is selected from the group consisting of:

i) JNJ 3026582 (RWJ 67657);

ii) JNJ 17089540 (RWJ 669307);

iii) JNJ 7583979 (RWJ 351958);

iv) SCIO-282 (SD 282); and

v) SCIO-469 (SD 469).

4 . The method of claim 1 , wherein the p38 MAP kinase inhibitor is a aryl-pyridinyl heterocycle.

5 . The method of claim 1 , wherein said p38 MAP kinase inhibitor is an indol-5-carboxamide.

6 . The method of claim 1 , wherein the formulation is administered in an amount effective to reduce pain.

7 . The method of claim 1 , wherein the formulation is administered in an amount effective to inhibit degradation of an extracellular matrix of the nucleus pulposus.

8 . The method of claim 1 , wherein the formulation is provided closely adjacent the outer wall of the annulus fibrosus.

9 . The method of claim 1 , wherein a portion of the nucleus pulposus is removed prior to transdiscally administering the formulation.

10 . The method of claim 1 , wherein the administration comprises providing the formulation in a depot at a location closely adjacent to an endplate of an adjacent vertebral body.

11 . The method of claim 1 , wherein the formulation further comprises at least one additional therapeutic agent.

12 . The method of claim 11 , wherein the additional therapeutic agent is selected from the group consisting of:

i) a growth factor,

ii) mesenchymal stem cells, adult stem cells and embryonic stem cells,

iii) an MMP antagonist,

iv) a monoclonal anti-TNFα antibody,

v) rapamycin,

vi) glycosaminoglycans.

vii) an antagonist of nitric oxide synthesis,

viii) an anti-oxidant,

ix) an anti-proliferative agent,

x) an anti-apoptotic agent,

xi) a COX-2 antagonist,

xii) a non-steroidal anti-inflammatory agent,

xiii) batimistat,

xiv) rhein,

xv) diacerein,

xvi) an IL-6 antibody, and

xvii) rhGDF-5.

xviii) glycosaminoglycans,

xvix) microparticles,

xx) a caspase inhibitor,

xxi) an inhibitor of pro-inflammatory interleukin,

xxii) an inhibitor of PLA 2 enzyme,

xxiii) tetracycline analogs and

xiv) IGFI and II.

13 . The method of claim 11 , wherein the additional therapeutic agent comprises mesenchymal stem cells.

14 . The method of claim 11 , wherein the additional therapeutic agent is selected from the group consisting of: rapamycin, JNJ 7706621, tolmetin, tepoxalin, suprofen, tiaprofenic acid; centella (ETCA), madecassoside, rhein, diacerein, feverfew, batimastat and ORC (Interceed).

15 . The method of claim 1 , wherein the formulation is predominantly released from the formulation through a sustained delivery device.

16 . A method of preventing or therapeutically treating a degenerating intervertebral disc, comprising the steps of:

a) determining a level of a pro-inflammatory protein within the disc,

b) comparing the level against a pre-determined level of the pro-inflammatory protein, and

c) injecting a p38 MAP kinase inhibitor into the disc, wherein the p38 MAP kinase inhibitor is selected from the group consisting of:

i) JNJ 3026582 (RWJ 67657);

ii) JNJ 17089540 (RWJ 669307);

iii) JNJ 7583979 (RWJ 351958);

iv) SCIO-282 (SD 282); and

v) SCIO-469 (SD 469).

17 . The method of claim 16 , wherein the pro-inflammatory protein is a p38 MAP kinase, interleukin-1, interleukin-4, interleukin-6, interleukin-8, or TNF-α.

18 - 37 . (canceled)