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Claims for Patent: 5,849,704

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Claims for Patent: 5,849,704

Title: Pharmaceutical formulation
Abstract:A pharmaceutical preparation comprising a growth hormone and histidine or a derivative of histidine as additive or buffering substance shows a very high stability against deamidation, oxidation and cleavage of peptide bonds. The stability of the product allows for the storing and shipment thereof in a lyophilized state or in the form of a dissolved or re-dissolved preparation at ambient temperature. Crystallization of growth hormone in the presence of histidine or a derivative thereof gives rise to a higher yield of crystals having a higher purity than known methods.
Inventor(s): S.o slashed.rensen; Hans Holmegaard (Virum, DK), Skriver; Lars (Ved.ae butted.k, DK), Hoelgaard; Annie Rassing (Holte, DK)
Assignee: Novo Nordisk A/S (Bagsvaerd, DK)
Application Number:08/458,386
Patent Claims: 1. A pharmaceutical composition in the form of a lyophilized powder comprising a growth hormone or a derivative thereof and histidine or histidine derivative, in which said derivative is selected from the group consisting of an amide or ester of histidine, imidazole, imidazole-4-acetic acid, des-amino-His, His--Leu, His--Ala, His--Lys, and His--Phe, in an amount of from about 0.1 to about 12 mg histidine per mg of growth hormone or a derivative thereof.

2. A pharmaceutical composition in the form of a buffered aqueous solution comprising a growth hormone or derivative thereof buffered with histidine or histidine derivative, in which said derivative is selected from the group consisting of an amide or ester of histidine, imidazole, imidazole-4-acetic acid, des-amino-His, His--Leu, His--Ala, His--Lys, and His--Phe at a concentration from about 1 mM to about 100 mM.

3. The pharmaceutical composition of claim 2 in which said composition has a pH from about 2 to about 8.

4. The pharmaceutical composition of claim 3 in which said composition has a pH from about 5 to about 7.

5. The pharmaceutical composition of claim 3 in which said composition has a pH of about 6.8.

6. The pharmaceutical composition of claim 2 in which the solution is buffered with histidine or derivative thereof at a concentration from about 1 mM to about 10 mM.

7. The pharmaceutical composition of claim 2 in which the solution is buffered with histidine or derivative thereof at a concentration from about 2 mM to about 6 mM.

8. The pharmaceutical composition of claim 2 in which the solution is buffered with histidine or derivative thereof at a concentration from about 3 mM to about 5 mM.

9. The pharmaceutical composition of claim 2 in which said composition further comprises a sugar alcohol or a disaccharide or a mixture thereof.

10. The pharmaceutical composition of claim 9 in which the sugar alcohol is mannitol.

11. The pharmaceutical composition of claim 9 wherein the disaccharide is sucrose or trehalose.

12. The pharmaceutical composition of claim 1 wherein the growth hormone is human growth hormone.

13. The pharmaceutical composition of claim 2 wherein the growth hormone is human growth hormone.

14. Crystalline growth hormone or a derivative thereof comprising histidine or histidine derivative, in which said derivative is selected from the group consisting of an amide or ester of histidine, imidazole, imidazole-4-acetic acid, des-amino-His, His--Leu, His--Ala, His--Lys, and His--Phe and a cation.

15. The crystalline growth hormone of claim 14 wherein the growth hormone is human growth hormone.

16. A method of preparing the crystalline growth hormone of claim 14 comprising the steps of:

a) forming a solution of growth hormone or a growth hormone derivative in a solvent and adding histidine or histidine derivative, in which said derivative is selected from the group consisting of an amide or ester of histidine, imidazole, imidazole-4-acetic acid, des-amino-His, His--Leu, His--Ala, His--Lys, and His--Phe using hydrochloric acid;

b) adding organic or inorganic cations to the solution of step (a);

c) crystallizing the solution of step (b) at a temperature from about 0.degree. C. to about 30.degree. C.; and

d) isolating the crystals formed in step (c).

17. The method of claim 16 wherein the solvent in step (a) is selected from the group consisting of short chained aliphatic, alicyclic or aromatic alcohols and ketones.

18. The method of claim 16 in which the solution of step (a) is adjusted to a pH from about 5 to about 8.

19. A method for treating a disorder in a patient affectable by growth hormone comprising treating the patient with an amount of the composition of claim 1 effective to treat said disorder.

20. A method for treating a disorder in a patient affectable by growth hormone comprising treating the patient with an amount of the composition of claim 2 effective to treat said disorder.

21. A method for treating a disorder in a patient affectable by growth hormone comprising treating the patient with an amount of the composition of claim 16 effective to treat said disorder.
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