Depot systems comprising glatiramer or pharmacologically acceptable salt thereof

Abstract

Long acting parenteral pharmaceutical compositions comprising a therapeutically effective amount of glatiramer are provided. In particular, the present invention provides a long acting pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate in depot form suitable for administering at a medically acceptable location in a subject in need thereof. The depot form is suitable for subcutaneous or intramuscular implantation or injection.

The invention claimed is: 
     
       1. A long acting parenteral pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, the composition being in a sustained release depot form which releases a therapeutically effective amount of the pharmaceutically acceptable salt of glatiramer over a period of about one week to about 6 months. 
     
     
       2. The pharmaceutical composition according to  claim 1 , comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer in depot form suitable for implantation at a medically acceptable location in a subject in need thereof. 
     
     
       3. The pharmaceutical composition according to  claim 1 , wherein the pharmaceutically acceptable salt of glatiramer is glatiramer acetate. 
     
     
       4. The pharmaceutical composition according to  claim 1 , in depot form suitable for subcutaneous or intramuscular implantation. 
     
     
       5. The pharmaceutical composition according to  claim 1 , wherein the glatiramer comprises L-alanine, L-glutamic acid, L-lysine, and L-tyrosine in molar ratios of about 0.14 glutamic acid, about 0.43 alanine, about 0.10 tyrosine and about 0.33 lysine. 
     
     
       6. The pharmaceutical composition according to  claim 1 , wherein the glatiramer comprises about 15 to about 100 amino acids. 
     
     
       7. The pharmaceutical composition according to  claim 1 , further comprising a pharmaceutically acceptable biodegradable or non-biodegradable carrier. 
     
     
       8. The pharmaceutical composition according to  claim 7 , wherein the carrier is selected from poly (D,L-lactide-co-glycolide) (PLGA), poly (D,L-lactide) (PLA), polyglycolides (PGA), polycaprolactone, polyhydroxybutyrate, polyorthoesters, polyalkaneanhydrides, gelatin, collagen, oxidized cellulose, and polyphosphazene. 
     
     
       9. The pharmaceutical composition according to  claim 1  in the form of microparticles prepared by a water-in oil-in water double emulsification process. 
     
     
       10. The pharmaceutical composition according to  claim 1  comprising an internal aqueous phase comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, a water immiscible polymeric phase comprising a biodegradable or non-biodegradable polymer and an external aqueous phase. 
     
     
       11. The pharmaceutical composition according to  claim 10 , wherein the water immiscible polymeric phase comprises a biodegradable polymer selected from poly (D,L-lactide) (PLA) and poly (D,L-lactide-co-glycolide) (PLGA). 
     
     
       12. The pharmaceutical composition according to  claim 10 , wherein the external water phase comprises a surfactant selected form polyvinyl alcohol (PVA), polysorbate, polyethylene oxide-polypropylene oxide block copolymers and cellulose esters. 
     
     
       13. The pharmaceutical composition according to  claim 1  in the form of biodegradable microspheres, non-biodegradable microspheres, implants of any suitable geometric shape, implantable rods, implantable capsules, implantable rings, or prolonged release gels or erodible matrices. 
     
     
       14. The pharmaceutical composition according to  claim 1 , wherein the composition provides equal or superior therapeutic efficacy to the commercially available daily injectable dosage forms of glatiramer acetate, with reduced incidence of side effects and/or with reduced severity of side effects at the local and/or systemic level. 
     
     
       15. The pharmaceutical composition according to  claim 14 , wherein the composition provides prolonged release or prolonged action of glatiramer in a subject as compared to a substantially similar dose of an immediate release formulation of glatiramer acetate. 
     
     
       16. A method of treating multiple sclerosis comprising the step of parenterally administering to a subject in need thereof a long acting pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, the composition being in a sustained release depot form which releases a therapeutically effective amount of the pharmaceutically acceptable salt of glatiramer over a period of about one week to about 6 months. 
     
     
       17. The method according to  claim 16 , wherein the long acting pharmaceutical composition comprises a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer in depot form suitable for implantation at a medically acceptable location in a subject in need thereof. 
     
     
       18. The method according to  claim 17 , comprising the step of implanting into a subject in need thereof the long acting pharmaceutical composition. 
     
     
       19. The method according to  claim 16 , comprising the step of subcutaneously or intramuscularly administering the pharmaceutical composition. 
     
     
       20. The method according to  claim 16 , wherein the pharmaceutical composition comprises glatiramer acetate. 
     
     
       21. The method according to  claim 20 , wherein the glatiramer acetate comprises L-alanine, L-glutamic acid, L-lysine, and L-tyrosine in the molar ratios of about 0.14 glutamic acid, about 0.43 alanine, about 0.10 tyrosine and about 0.33 lysine. 
     
     
       22. The method according to  claim 21 , wherein the glatiramer comprises about 15 to about 100 amino acids. 
     
     
       23. The method according to  claim 16 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable biodegradable or non-biodegradable carrier. 
     
     
       24. The method according to  claim 16 , wherein the pharmaceutical composition is in the form of microparticles prepared by a water-in oil-in water double emulsification process. 
     
     
       25. The method according to  claim 16 , wherein the pharmaceutical composition comprises an internal aqueous phase comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, a water immiscible polymeric phase comprising a biodegradable or non-biodegradable polymer and an external aqueous phase. 
     
     
       26. The method according to  claim 16 , wherein the pharmaceutical composition is in the form of biodegradable microspheres, non-biodegradable microspheres, implants of any suitable geometric shape, implantable rods, implantable capsules, or implantable rings, prolonged release gels or erodible matrices. 
     
     
       27. The method according to  claim 16 , wherein the pharmaceutically acceptable salt of glatiramer is glatiramer acetate and the depot form contains between 20 mg and 750 mg of glatiramer acetate.  
     
     
       28. The method according to  claim 27 , comprising administering the depot form at a dosing regimen ranging from once every 2 weeks to once monthly.  
     
     
       29. The method according to  claim 23 , wherein the carrier is selected from poly (D,L-lactide-co-glycolide) (PLGA), poly (D,L-lactide) (PLA), polyglycolides (PGA), polycaprolactone, polyhydroxybutyrate, polyorthoesters, polyalkaneanhydrides, gelatin, collagen, oxidized cellulose, and polyphosphazene.  
     
     
       30. A method of treating multiple sclerosis comprising the step of parenterally administering to a subject in need thereof a long acting pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, and a pharmaceutically acceptable biodegradable or non-biodegradable carrier which provides the composition in a sustained release depot form which releases a therapeutically effective amount of the pharmaceutically acceptable salt of glatiramer over a period of one week to 6 months, wherein the pharmaceutically acceptable salt of glatiramer is glatiramer acetate, the depot form contains between 20 mg and 750 mg of glatiramer acetate and the carrier comprises a poly (D,L-lactide-co-glycolide) (PLGA).  
     
     
       31. A long acting parenteral pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, and a pharmaceutically acceptable biodegradable or non-biodegradable carrier which provides the composition in a sustained release depot form which releases a therapeutically effective amount of the pharmaceutically acceptable salt of glatiramer over a period of about one week to about 6 months, wherein the pharmaceutically acceptable salt of glatiramer is glatiramer acetate, the depot form contains between 20 mg and 750 mg of glatiramer acetate, and the carrier comprises a poly (D,L-lactide-co-glycolide) (PLGA), wherein the depot form is prepared as a suspension for injection, and the suspension comprises microparticles.  
     
     
       32. The pharmaceutical composition according to  claim 31 , wherein the microparticles comprise double emulsion droplets comprising an internal aqueous phase comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, a water immiscible polymeric phase comprising a biodegradable or non-biodegradable polymer and an external aqueous phase.  
     
     
       33. The pharmaceutical composition according to  claim 31 , wherein preparation of the suspension for injection comprises, preparing microparticles comprising glatiramer acetate and PLGA by a water-in-oil-in-water double emulsification, drying the microparticles to form dried microparticles, and reconstituting the dried microparticles to form the suspension of the sustained release depot form for administration by injection.  
     
     
       34. A method for treating multiple sclerosis, comprising the step of injecting into a subject in need thereof the pharmaceutical composition according to  claim 1 .  
     
     
       35. A method for treating multiple sclerosis, comprising the step of injecting into a subject in need thereof the pharmaceutical composition according to  claim 31 .