FIELD OF THE INVENTION

The present invention provides linezolid formulations, methods and manufactures useful for chronic low back pain treatment. In one aspect of the invention, the linezolid formulation comprises linezolid form II suspension, iohexol and poloxamer 407, and is injectable.

BACKGROUND OF THE INVENTION

Chronic Low back pain (CLBP) is common among the general population worldwide. A positive association between Modic changes (bone edema) on MRI and non-specific LBP with a mean odds ratio (OR) of 4.5 has been observed. Jensen et al. reviewed that the prevalence for any type of Modic changes (e.g., Types I-III) in patients with non-specific CLBP was 46% as opposed to 6% in the general population (Jensen et al.,Eur. Spine J.2008, 17:1407-1422).

Modic changes, characterized by edema (or inflammation) in vertebrae, are likely caused by low-grade infection of the disc tissue, where disc/endplate damage and the persistence of an inflammatory stimulus create predisposing conditions.Propionibacterium acnes(P. acnes) inside nonpyogenic intervertebral discs has been shown to be one pathogen causing Modic changes (e.g., Type I) and nonspecific low back pain (Stirling et al.Lancet,2001, 357:2024-2025; Agarwal et al.Spine J.2010, 10: S45-S46; Albert et al.,Eur Spine J.,2013, 22(4): 690-696; Capoor et al.,PLoS One,2016, 11(8):e0161676. doi: 10.1371; and Capoor et al.,PLos One,2017, 12(4): e0174518.doi:10.1371). Disc cells can develop an inflammatory response toP. acnesinfection (Dudli et al.,Eur Spine J.,2017, Sep. 7. doi: 10.1007/s00586-017-5291-4).P. acnesisolated from a patient associated with Modic changes and disc degeneration, when inoculated into the intervertebral discs, can induce inflammatory reaction, intervertebral disc degeneration and Modic changes (Chen et al.,Biomed Res Int.2016: 9612437. doi: 10.1155/2016/9612437. Epub 2016 Jan. 26; and Chen et al.,Int Orthop.2016, 40(6):1291-1298; and Dudli et al.,J Orthop Res.2016, 34(8):1447-1455). Studies done in animals also show thatP. acnesinfection in disc can induce degeneration of the disc and Modic changes (Zamora et al.,Orthop Traumatol Surg Res.,2017, 103(5): 795-799; Shan et al.,Spine,2017, Apr. 10. doi: 10.1097/BRS.0000000000002192; and Shan et al, J Bone Joint Am., 2017, 99(6): 472-481). Strains ofP. acnesassociated with tissue infections also express hyaluronic acid degrading enzymes which may contribute to disc degeneration. (Nazipi et. al., Microorganisms. 2017 Sep. 12; 5(3). pii: E57. doi: 10.3390/microorganisms5030057).

It is hypothesized that anaerobic bacteria (likeP. acnes) from mouth and skin may gain access to the disc. Local inflammation in the adjacent bone may be a secondary effect due to cytokine and propionic acid production, where the infection is in the disc and the Modic change is a “side effect” manifested in the bone (Albert et al.,Eur Spine J.,2013, 22(4): 690-696).

Antibiotic therapy may be effective in the treatment of CLBP associated with Modic changes). Several studies have shown that oral administration of antibiotics such as amoxicillin-clavulanate can have a clinically important and statistically significant (p<0.001) improvement in all outcome measures in patients with chronic LBP (Albert et al.,Br. J. Sports Med.2008, 42(12): 969-973; and Albert et al.Eur Spine J.2013, 22(4): 697-707). These results provided support for the hypothesis that bacterial infection may play a role in CLBP with Modic changes.

Although several non-surgical treatment approaches including intradiscal injections of steroid, anti-TNF-α antibody and bisphosphonates have demonstrated some short-term efficacy in non-replicated clinical studies in reducing Modic changes and CLBP, none of these approaches is successful and causes controversial results. On this background, there is a need in the art for modalities to address the treatment, alleviation, prevention, and/or mitigation of pain found to be coincident with diseases, conditions or disorders of the bones, joints, ligaments and/or tendons, especially those associated with Modic changes or bone edema. The present invention provides linezolid formulations to fill this need. Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.P. acnesclinical isolates which are resistant to linezolid (MIC>4 μg/ml) have not been widely reported. The linezolid formulations provide an effective delivery of linezolid to the diseased disc and vertebrae, therefore improve treatment efficacy of Modic changes and CLBP.

SUMMARY OF THE INVENTION

The present invention provides injectable formulations suitable for delivering linezolid to the infected spinal sites for treating, preventing, ameliorating, and/or mitigating one or more types of pain, or phenotypic presentations coincident with a clinical condition of the bones, joints, ligaments, or tendons. Kits, packages and methods of manufacturing and using the same are also provided.

In accord with the present invention, linezolid formulations are made as suspensions which form hydrogels in situ in responding to the warm body temperature. The formulation of the present invention is thermosensitive and injectable.

In some embodiments, the formulation of the present invention comprises an effective amount of linezolid. In some aspects, linezolid is linezolid form II which is prepared as particle suspension in the formulation. Linezolid may be loaded to the delivery vehicle (i.e., hydrogel) to form suspension with about 1% to about 20%, or preferably about 2.5% to about 20% by weight or by volume of the final formulation. In some examples, the suspension formulation may comprise about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, about 75 mg/ml, about 80 mg/ml, about 85 mg/ml, about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about 150 mg/ml, or about 200 mg/ml linezolid.

In some embodiments, the linezolid formulation of the present invention comprises poloxamer as the delivery vehicle which forms hydrogel in responding to the temperature increase. In some aspects, the poloxamer is Poloxamer 407. The linezolid formulation of the present invention may comprise Poloxamer 407 with about 9.5% to about 17% by weight of the formulation, or about 9.5% to about 14.5% by weight of the formulation, or about 10.5% to about 13.5% by weight of the formulation, or at a concentration of about 115 mg/ml to about 207 mg/ml in the formulation, or at a concentration of about 130 mg/ml to about 165 mg/ml in the formulation. Preferably the linezolid formulation may comprise Poloxamer 407 with about 10.8% to about 12.8% by weight of the formulation, or at a concentration of about 130 mg/ml to 156 mg/ml in the formulation.

In some embodiments, the linezolid formulation of the present invention comprises a radio-opaque dye. In some aspects, the agent is iohexol. The linezolid formulation may comprise iohexol with about 14% to about 59% by weight of the formulation, or about 14% to about 40% by weight of the formulation, or at a concentration of about 165 mg/ml to about 718 mg/ml in the formulation, or at a concentration of about 200 mg/ml to about 450 mg/ml in the formulation. Preferably the linezolid formulation may comprise iohexol with about 17% to about 30% by weight of the formulation, or at a concentration of about 206 mg/ml to 364 mg/ml in the formulation.

In one preferred embodiment, the linezolid formulation comprises linezolid form II at about 2.5% to about 20% by weight or by volume of the final formulation and a delivery vehicle (aka the diluent) comprising poloxamer 407 at about 10.8% to about 12.8% by weight of the formulation and iohexol at about 17% to about 30% by weight of the formulation. The formulation is a linezolid suspension. The linezolid formulation is injectable and has a sol-gel transition temperature at about 26° C. to about 36° C.

Formulations of the present invention may be applied to a subject in need in the lumbar intervertebral disc and/or the adjacent vertebrae, ligaments, muscles, tendons and joints, and the application is carried out by open surgery or by injection or by means of a microsurgical or percutaneous technique.

In some embodiments, the present invention provides methods of manufacture and use of the linezolid formulations. In some examples, the linezolid formulation may be packed separately including a dose of linezolid powders and a solution of delivery vehicle comprising poloxamer 407 and iohexol with an optimized concentration ratio. The suspension can be prepared by mixing the linezolid power and poloxamer vehicle before administration. Provided in the present invention also includes a kit comprising the present compositions, vehicles and a syringe and/or needle for administering the sterile injectable formulation.

