Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same

• US 6,828,305 B2
• Filed: 06/04/2001
• Issued: 12/07/2004
• Est. Priority Date: 06/04/2001
• Status: Expired due to Fees

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Ekwuribe, Nnochiri N., Odenbaugh, Amy L., Price, Christopher H., Ansari, Aslam M.
• Primary Examiner(s): RUSSEL, JEFFREY E
• Application Number:
  US09/873,757
• Publication Number:
  US 20030027995A1
• Time in Patent Office: 1,282 Days
• Field of Search: 530/324, 530/345, 530/399, 530/410, 514/2, 514/12, 514/21, 528/425, 554/227, 562/587, 568/613, 568/618, 568/622, 568/623
• US Class Current: 514/5.5
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: C07K 14/61 Growth hormone [GH], i.e. somatotropin

Abstract

Mixtures of conjugates in which each conjugate in the mixture comprises a growth hormone drug coupled to an oligomer that includes a polyalkylene glycol moiety wherein the mixtures have a molecular weight distribution with a standard deviation of less than about 22 Daltons are disclosed. Methods of treating growth hormone deficiency in a subject in need of such treatment and methods of accelerating the growth rate of an animal arc also disclosed. Processes for synthesizing substantially monodispersed mixtures of conjugates wherein each conjugate comprises a growth hormone drug coupled to an oligomer that comprises a polyethylene glycol moiety are further provided.

Claims

1. A mixture of conjugates each comprising a human growth hormone drug coupled to an oligomer that comprises a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms, said mixture having a molecular weight distribution with a standard deviation of less than about 22 Daltons.

2. The mixture of claim 1, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

3. The mixture of claim 1, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 4, 5 or 6 carbon atoms.

4. A method of treating human growth hormone deficiency in a subject in need of such treatment, said method comprising:

administering an effective amount of a mixture of conjugates, each comprising a human growth hormone drug coupled to an oligomer that comprises a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms, said mixture having a molecular weight distribution with a standard deviation of less than about 22 Daltons, to the subject to treat the human growth hormone deficiency.

5. The method of claim 4, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

6. The method of claim 4, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 4, 5 or 6 carbon atoms.

7. A method of accelerating the growth rate of a human subject, said method comprising:

administering to the human subject a mixture of conjugates each comprising a human growth hormone drug coupled to an oligomer that comprises a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms, said mixture having a molecular weight distribution with a standard deviation of less than about 22 Daltons, in an amount sufficient to accelerate the human subject'"'"'s growth rate.

8. The method of claim 7, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

9. The method of claim 7, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 4, 5 or 6 carbon atoms.

10. A substantially monodispersed mixture of conjugates, each conjugate comprising a human growth hormone drug coupled to an oligomer that comprises a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms.

11. The mixture of claim 10, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

12. The mixture of claim 10, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 2 to 18 carbon atoms.

13. A mixture of conjugates each comprising a human growth hormone drug coupled to a polymer having a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms, wherein the mixture has a dispersity coefficient (DC) greater than 10,000 where $\mathrm{DC}=\frac{{(\sum _{}^{}}^{}}{}$

i=1n

Ni

Mi)2∑

i=1n

Ni

Mi2

∑

i=1n

Ni-(∑

i=1n

Ni

Mi)2

wherein;

n is the number of different molecules in the sample;

N_i is the number of i^th molecules in the sample; and

M_i is the mass of the i^th molecule.

14. The mixture of claim 13, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

15. A mixture of conjugates each comprising a human growth hormone drug coupled to a polymer having a polyalkylene glycol moiety and a lipophilic moiety that comprises natural fatty acid moieties having 4, 5 or 6 carbon atoms, wherein the mixture has a dispersity coefficient (DC) greater than 10,000 where $\mathrm{DC}=\frac{{(\sum _{}^{}}^{}}{}$

i=1n

Ni

Mi)2∑

i=1n

Ni

Mi2

∑

i=1n

Ni-(∑

i=1n

Ni

Mi)2

wherein;

n is the number of different molecules in the sample;

N_i is the number of i^th molecules in the sample; and

M_i is the mass of the i^th molecule.

16. The mixture of claim 15, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms.

17. The mixture of claim 15, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

18. A mixture of conjugates in which each conjugate:

(a) comprises a human growth hormone drug coupled to an oligomer comprising a polyalkylene glycol and a lipophilic moiety that comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms; and

(b) has the same number of polyalkylene glycol subunits.

19. The mixture off claim 18, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

20. The method of claim 18, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 4, 5 or 6 carbon atoms.

21. A method of treating human growth hormone deficiency in a subject in need of such treatment, said method comprising:

administering an effective amount of a mixture of conjugates, each comprising a human growth hormone drug coupled to an oligomer that comprises a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 4, 5 or 6 carbon atoms, said mixture having a molecular weight distribution with a standard deviation of less than about 22 Daltons, to the subject to treat the human growth hormone deficiency.

22. The method of claim 21, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

23. A method of accelerating the growth rate of a human subject, said method Comprising:

administering to the human subject a mixture of conjugates each comprising a human growth hormone drug coupled to an oligomer that comprises a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 4, 5 or 6 carbon atoms, said mixture having a molecular weight distribution with a standard deviation of less than about 22 Daltons, in an amount sufficient to accelerate the human subject'"'"'s growth rate.

24. The method of claim 23, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

25. A substantially monodispersed mixture of conjugates, each conjugate comprising a human growth hormone drug coupled to an oligomer that comprises a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 4, 5 or 6 carbon atoms.

26. The mixture of claim 25, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms.

27. The mixture of clam 25, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

28. A mixture of conjugates each comprising a human growth hormone drug coupled to a polymer having a polyalkylene glycol moiety and a lipophilic moiety that comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 4, 5 or 6 carbon atoms, wherein the mixture has a dispersity coefficient (DC) greater than 10,000 where $\mathrm{DC}=\frac{{(\sum _{}^{}}^{}}{}$

i=1n

Ni

Mi)2∑

i=1n

Ni

Mi2

∑

i=1n

Ni-(∑

i=1n

Ni

Mi)2

wherein;

n is the number of different molecules in the sample;

N_i is the number of i^th molecules in the sample; and

M_i is the mass of the i^th molecule.

29. The mixture of claim 28, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 1 to 28 carbon atoms.

30. The mixture of claim 28, wherein the lipophilic moiety comprises one or more linear, saturated or unsaturated alkyl moieties having 2 to 12 carbon atoms.

31. A mixture of conjugates in which each conjugate:

(a) comprises a human growth hormone drug coupled to an oligomer comprising a polyalkylene glycol and a lipophilic moiety that comprises one or more linear, saturated or unsaturated natural fatty acid moieties having 4, 5 or 6 carbon atoms; and

(b) has the same number of polyalkylene glycol subunits.