Stable MIA/CD-RAP formulation
The present invention relates to stable aqueous formulations comprising at least 5 mg/mL CD-RAP and a charged amino acid, said amino acid preferably having a net charge at a pH between about 6 and 8. The ingredients of the formulation preferably provide stability over repeated freeze-thaw cycles. In a preferred aspect, the formulation is for use in therapy, preferably for use in the treatment of inflammatory disorders, preferably osteoarthritis. Furthermore, a kit comprising the formulation of the invention is provided.
1. A stable aqueous formulation comprising at least 5 mg/mL of cartilage-derived retinoic acid-sensitive protein (CD-RAP) and at least one of (i)-(viii):
(i) 50 mM TRIS chloride and 2.5% glutamate;
(ii) 50 mM histidine and 2.5% (w/v) glycine, 2.5% (w/v), glutamate (w/v) or 2.5% lysine (w/v);
(iii) 300 mM histidine chloride pH 6.0;
(iv) 50, 100, 200 or 300 mM histidine phosphate pH 6.0;
(v) 350 mM arginine chloride pH 6.0;
(vi) 350 mM arginine phosphate pH 6.0;
(vii) 350 mM arginine phosphate pH 7.4; or
(viii) 300 mM potassium glutamate pH 6.0,
wherein the CD-RAP protein is directly dissolved therein, and where the CD-RAP does not lose more than 15% of its biological activity during storage relative to activity of CD-RAP at beginning of storage, wherein storage is for at least one month.
2. The formulation of claim 1 , wherein any of said amino acids of (i)-(viii) has a net charge at a pH between about 6 and 8.
3. The formulation of claim 1 , which comprises a buffer.
4. The formulation of claim 1 , which comprises a tonicity modifier.
5. The formulation of claim 1 , which comprises a stabilizer.
6. The formulation of claim 1 , further comprising an excipient.
7. The formulation of claim 1 , wherein said formulation has a pH between about 6 and 8.
8. The formulation of claim 1 , which is in a freeze dried, lyophilized or spray-dried form.
9. The formulation of claim 1 , wherein the ingredients of the formulation provide stability over repeated freeze-thaw cycles.
10. A kit comprising the formulation of claim 1 .
11. The formulation of claim 1 , which comprises at least 30 mg/mL CD-RAP.
12. The formulation of claim 1 , which comprises (iv) 50, 100, 200 or 300 mM histidine phosphate pH 6.0.
13. The formulation of claim 1 , wherein storage is for at least six months.
14. The formulation of claim 1 , wherein storage is for a period in the range of one month to two years.
15. The formulation of claim 1 , which comprises at least 7.5 mg/mL CD-RAP.
16. The formulation of claim 15 , which comprises at least 10 mg/mL CD-RAP.
17. A stable aqueous formulation comprising at least 5 mg/mL of cartilage-derived retinoic acid-sensitive protein (CD-RAP) and at least one of (i)-(viii):
(i) 50 mM TRIS chloride and 2.5% glutamate;
(ii) 50 mM histidine and 2.5% (w/v) glycine, 2.5% (w/v), glutamate (w/v) or 2.5% lysine (w/v);
(iii) 300 mM histidine chloride pH 6.0;
(iv) 50, 100, 200 or 300 mM histidine phosphate pH 6.0;
(v) 350 mM arginine chloride pH 6.0;
(vi) 350 mM arginine phosphate pH 6.0;
(vii) 350 mM arginine phosphate pH 7.4; or
(viii) 300 mM potassium glutamate pH 6.0,
wherein the CD-RAP protein is directly dissolved therein, and where the CD-RAP does not lose more than 15% of its biological activity during freeze-thawing or after freeze-thawing.
18. The formulation of claim 17 , which comprises at least 30 mg/mL CD-RAP.