The present invention relates to conjugates of biocompatible polymers and hGH, particularly PEG-hGH, where the activated biocompatible polymer is conjugated to a carboxyl group of hGH at a molar ratio of 2:1 or less, preferably 1:1, methods of preparation, and related pharmaceutical compositions. Th
The present invention relates to conjugates of biocompatible polymers and hGH, particularly PEG-hGH, where the activated biocompatible polymer is conjugated to a carboxyl group of hGH at a molar ratio of 2:1 or less, preferably 1:1, methods of preparation, and related pharmaceutical compositions. The PEG-hGH conjugates have up to 20% of the activity of the native hGH while the in vivo half life is increased 10 fold. The PEG-hGH conjugates may be used therapeutically to treat growth retardation or growth failure, especially short stature in children, and conditions related to aging.
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What is claimed is: 1. A conjugate of biocompatible polymer-human Growth Hormone (hGH), wherein the biocompatible polymer is conjugated to a carboxyl group of hGH at a molar ratio of 2:1 or less. 2. The conjugate according to claim 1, wherein the biocompatible polymer is selected from the group
What is claimed is: 1. A conjugate of biocompatible polymer-human Growth Hormone (hGH), wherein the biocompatible polymer is conjugated to a carboxyl group of hGH at a molar ratio of 2:1 or less. 2. The conjugate according to claim 1, wherein the biocompatible polymer is selected from the group consisting of PEG-20000 and PEG-30000. 3. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the conjugate according to claim 1 and a pharmaceutically acceptable carrier. 4. The conjugate of claim 1, wherein the carboxyl group is the C-terminus of hGH. 5. The conjugate of claim 1, wherein the activity of the conjugate is 10-20% of the activity of an unconjugated hGH protein. 6. The conjugate of biocompatible polymer-hGH according to claim 1, wherein the biocompatible polymer is conjugated to the carboxyl group of the hGH at a molar ratio of 1:1. 7. The conjugate of claim 6, wherein the biocompatible polymer is PEG. 8. A method of preparing a conjugate of biocompatible polymer-hGH comprising: (a) providing a purified hGH protein; (b) activating a biocompatible polymer with the stepwise addition of a coupling reagent; and (c) conjugating the activated biocompatible polymer to a carboxyl group of the hGH at a molar ratio of 2:1 or less, wherein the molar ratio of the hGH to the activated biocompatible polymer is 1:1 to 1:20, the ratio of the hGH to the coupling reagent is 1:1 to 1:50, and pH is in the range of 2 to 5. 9. The method according to claim 8, wherein the biocompatible polymer is activated with a reactive functional group which is able to react with a carboxylic acid and/or a reactive carbonyl group. 10. The method according to claim 8, wherein the biocompatible polymer is selected from the group consisting of PEG-20000 and PEG-30000. 11. The method of claim 8, wherein the carboxyl group is the C-terminus of hGH. 12. The method of claim 8, further comprising providing the purified hGH by the steps of: (i) producing hGH in a recombinant host; (ii) concentrating hGH using ammonium sulfate; and (iii) purifying the concentrated hGH by anionic ion exchange chromatography. 13. The method of claim 12, wherein the chromatography is performed as a single step. 14. A method of treating growth failure or growth retardation by administering an effective amount of the conjugate of claim 1 to a patient in need thereof. 15. The method of claim 14, wherein the biocompatible polymer is PEG. 16. The method of claim 15, wherein the PEG-hGH is conjugated at a molar ratio of 1:1. 17. The method of claim 14, wherein the conjugate has 10-20% of the activity of unconjugated hGH protein. 18. The method according to claim 14, wherein the growth failure or growth retardation is due to hormone deficiency, chronic renal disease, Turner's syndrome, cachexia or AIDS wasting. 19. The method according to claim 14, wherein the conjugate is administered in combination with a pharmaceutically acceptable carrier. 20. The method according to claim 14, wherein the administration is done by injection. 21. The method according to claim 14, wherein the administration is oral. 22. The method according to claim 14, wherein the composition is administered no more than twice per week to the patient in need thereof. 23. A method of treating short stature in children by administering an effective amount of a composition comprising PEG-hGH to a patient in need thereof at a frequency of no more than twice/week, wherein the PEG is conjugated to a C-terminus carboxyl group of hGH at a molar ratio of 1:1 and the PEG-hGH has 10-20% of the activity of unconjugated hGH. 24. A method of treating adverse effects associated with aging selected from the group consisting of decrease in lean muscle, increase in blood pressure, increase in cholesterol, increase in body fat, loss of skin tone, and decrease in bone density by administering an effective amount of a composition comprising PEG-hGH to a patient in need thereof, wherein the PEG is conjugated to a carboxyl group of hGH at a molar ratio of 1:1. 25. A kit comprising: the conjugate of claim 1 in lyophilized form; a pharmaceutically acceptable carrier for reconstitution of the conjugate; and a delivery device for delivery of the reconstituted conjugate to a patient in need thereof. 26. The kit of claim 25, further comprising: a skin antiseptic; and an instruction sheet. 27. The kit of claim 26, wherein the instruction sheet directs administration of the biocompatible polymer-hGH conjugate composition no more than twice per week to the patient in need thereof. 28. A kit comprising the conjugate of claim 1 preloaded in a syringe.
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