Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-01-08
2002-09-17
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S004300, C514S866000, C530S303000, C530S304000
Reexamination Certificate
active
06451762
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to protracted acting, water-soluble aggregates of derivatives of human insulin, derivatives of human insulin capable of forming such aggregates, pharmaceutical compositions containing them, and to the use of such aggregates in the treatment of diabetes
BACKGROUND OF THE INVENTION
Diabetes is a general term for disorders in man having excessive urine excretion as in diabetes mellitus and diabetes insipidus. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is more or less completely lost. About 2% of all people suffer from diabetes.
Since the introduction of insulin in the 1920's, continuous strides have been made to improve the treatment of diabetes mellitus. To help avoid extreme glycaemia levels, diabetic patients often practice multiple injection therapy, whereby insulin is administered with each meal. Many diabetic patients are treated with multiple daily insulin injections in a regimen comprising one or two dailyl injections of a protracted insulin to cover the basal requirement supplemented by bolus injections of a rapid acting insulin to cover the meal-related requirements.
Protracted insulin compositions are well known in the art. Thus, one main type of protracted insulin compositions comprises injectable aqueous suspensions of insulin crystals or amorphous insulin. In these compositions, the insulin compounds utilised typically are protamine insulin, zinc insulin or protamine zinc insulin.
When human or animal insulin is brought to form higher associated forms, e.g. in the presence of Zn
2+
-ions, precipitation in the form of crystals or amorphous product is the result (Brange, Galenics of Insulin, pp. 120-27, Springer Verlag 1987). Thus, at pH 7 and using 6 Zn
2+
/hexamer of porcine insulin the result is an almost complete precipitation from solution (Grant, Biochem J. 126, 433-440, 1972). The highest soluble aggregate suggested is composed of 4 hexameric units, corresponding to a molecular weight of about 144 kDa. Blundell et al. (Diabetes 21 (Suppl. 2), 492-505, 1972) describe the soluble unit of porcine insulin in the presence of Zn
2+
at pH 7 as a hexamer. Early ultracentrifugation studies at pH 2 showed the insulin dimer, Mw 12 kDa, to be the prevailing species (Jeffrey, Nature 197, 1104-1105, 1963; Jeffrey, Biochemistry 5, 489-498, 1966; Jeffrey, Biochemistry 5, 3820-3824, 1966). Fredericq, working at pH 8 and using 0.4-0.8% (w/w) Zn
2+
relative to insulin, reported a molecular weight of 72 kDa, corresponding to a dodecameric structure and, using 1% Zn, molecular weights of about 200-300 kDa (Arch. Biochem Biophys. 65, 218-28, 1956). A comprehensive review of the association states of animal insulin is found in Blundell et al. (Adv. Protein Chem. 26, 297-330, 1972).
Certain drawbacks are associated with the use of insulin suspensions. Thus, in order to secure an accurate dosing, the insulin particles must be suspended homogeneously by gentle shaking before a defined volume of the suspension is withdrawn from a vial or expelled from a cartridge. Also, for the sitorage of insulin suspensions, the temperature must be kept within more narrow limits than for insulin solutions in order to avoid lump formation or coagulation.
While it was earlier believed that protamines were non-immunogenic, it has now turned out that protamines can be immunogenic in man and that their use for medical purposes may lead to formation of antibodies (Samuel et al., Studies on the immunogenicity of protamines in humans and experimental animals by means of a micro-complement fixation test, Clin. Exp. Immunol. 33, pp. 252-260 (1978)).
Also, evidence has been found that the protamine-insulin complex is itself immunogenic (Kurtz et al., Circulating IgG antibody to protamine in patients treated with protamine-insulins. Diabetologica 25, pp. 322-324 (1983)). Therefore, with some patients the use of protracted insulin compositions containing protamines must be avoided.
Another type of protracted insulin compositions are solutions having a pH value below physiological pH from which the insulin will precipitate because of the rise in the pH value when the solution is injected. A drawback is that the solid particles of the insulin act as a local irritant causing inflammation of the tissue at the site of injection.
WO 91/12817 (Novo Nordisk A/S) discloses protracted, soluble insulin compositions comprising insulin complexes of cobalt(III). The protraction of these complexes is only intermediate and the bioavailability is reduced.
Soluble insulin derivatives containing lipophilic substituents linked to the &egr;-amino group of a lysine residue in any of the positions B26 to B30 have been described in e.g. WO 95/07931 (Novo Nordisk A/S), WO 96/60107 (Novo Nordisk A/S) and WO 97/31022 (Novo Nordisk A/S). Such derivatives have a protracted action after subcutaneous injection as compared to soluble human insulin, and this protracted action has been explained by a reversible binding to albumin in subcutis, blood and peripheral tissue (Markussen, Diabetologia 39, 281-288, 1996; Kurzhials, Biochem J. 312, 725-731, 1995; Kurzhals, J. Pharm Sciences 85, 304-308, 1996; and Whittingham, Biochemistry 36, 2826-2831, 1997).
However, we have now discovered a new mechanism of prolonging the action of some of the soluble insulin derivatives. The new mechanism is based on the partly or fully formation of soluble aggregated forms of the derivatives, featuring a size larger than aldolase (Mw=158 kDa) in a defined gel filtration system.
REFERENCES:
patent: 5866538 (1999-02-01), Norup et al.
patent: 6011077 (2000-01-01), Havelund et al.
patent: WO 91/12817 (1991-09-01), None
patent: WO95/07931 (1995-03-01), None
patent: WO 95/07931 (1995-03-01), None
patent: WO 96/00107 (1996-01-01), None
patent: WO 96/04307 (1996-02-01), None
patent: WO 97/31022 (1997-08-01), None
Kurtzhals et al., (1996) J. of Pharmaceutical Sciences 85(3):304-308.
Sluzky et al., (1991) Proc. Nat. Acad. Sci. USA 88:9377-9381.
File medline on STN. No. 90282737. Rafter, G.W. Reaction of insulin with reduced gluthathione', Biochemistry International, vol. 20, No. 4, pp. 817-820. 1990 abstract only.*
Katakam et al., PDA Joournal of Pharmaceutical Science & Technology, vol. 49, No. 4, pp. 160-165 (1995).
Brange et al., Journal of Pharmaceutical Sciences, vol. 86, No. 5, pp. 517-525 (1997).
Samuel et al., Clin. exp. Immunol., vol. 33, pp. 252-260 (1978).
Kurtzhals et al., Journal of Pharmaceutical Sciences, vol. 85, No. 3, pp. 304-308 (1996).
Markussen et al., Diabetologia, vol. 39, pp. 281-288 (1996).
Kurtzhals et al., Biochem. J., vol. 312, pp. 725-731 (1995).
Eugne Fredericq, Archives of Biochemistry and Biophysics, vol. 65, pp. 218-228 (1956).
Whittingham et al., Biochemistry, vol. 36, pp. 2826-2831 (1997).
Jeffrey et al., Nature, vol. 197, No. 4872, pp. 1104-1105 (1963).
Blundell et al., Diabetes 21 (Suppl. 2), pp. 492-505 (1972).
Grant et al., Biochem. J., vol. 126, pp. 433-440 (1972).
Jeffrey et al., Biochemistry, vol. 5, No. 12,pp. 3820-3824 (1996).
Jeffrey et al., Biochemistry, vol. 5, No. 2, pp. 489-498 (1966).
Blundell et al., Adv. Protein Chem., vol. 26, pp. 297-330 (1972).
Kurtz et al., Diabetologia, vol. 25, pp. 322-324 (1983).
Balschmidt Per
Havelund Svend
Høeg-Jensen Thomas
Jonassen Ib
Bork, Esq. Richard W.
Gupta Anish
Low Christopher S. F.
Novo Nordisk A S
Reza Green, Esq.
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